HUT65384A - Process for preparation of novel benzopyrane derivatives and pharmaceutical compositions containing them - Google Patents

Description

The present invention relates to novel benzopyran derivatives and their pharmaceutically acceptable salts which possess valuable therapeutic properties, including potassium channel activating and 5-lipoxygenase inhibiting activity. Potassium channel activating agents exhibit many valuable properties, of which the smooth muscle relaxant and bronchodilator are exemplified. These compounds are thus useful in the treatment of disorders such as circulatory, respiratory disorders, cerebral spasms, seizures, peripheral vascular obstruction and disorders of the gastrointestinal tract, uterus, and kidneys which require treatment with a smooth muscle relaxant. 5-Lipoxygenase inhibitors also exhibit a number of valuable effects, such as those used to treat pain, inflammatory and allergic conditions, proliferative disorders, ulcerative colitis and seizures.

The compounds of the invention are also useful in the treatment of glaucoma, epilepsy, psycho-depressive states and baldness.

The compounds of the present invention are various benzopyran derivatives which, for example, activate the potassium channel and inhibit 5-lipoxygenase. Structurally somewhat similar compounds are described in European Patent Applications 277,611, 277,612, 312,432, 339,562, 346,724, 375,449, and 410,208 in J.Med.Chem. 3.3, 1529-41 and 3028-34 (1990) and Trends in Pharm. Science, IX, 417-22 (1990).

An object of the present invention is to provide compounds of formula I in the formula

-3 ····· ······ ·· • · · · · · · «· · · '·· · · · r! and R ² are each independently hydrogen or lower alkyl, or together with the carbon to which they are attached form C 3-8 cycloalkyl;

R ^{2 is} hydrogen, halogen, lower-carbon fluoroalkyl, cyano or nitro, (a), (b) or (c), r 5 and R 4 are each independently hydrogen or lower-alkyl; and

R? A group of the formula -NR®R® wherein

R @ 3 is hydrogen, lower alkyl, lower alkoxy, hydroxy or lower hydroxyalkyl; and

R® hydrogen, lower alkyl, lower alkyl, hydroxy-alkyl, _-SO2 ^R10, _-CO2 ^R10, -C (O) NR ¹¹ R ^12, -C (S) R ¹¹ R ¹² or -C (O) ² R 1 group of formula I wherein Rio is lower alkyl;

hydrogen or lower alkyl; and R 1 ² is hydrogen, lower alkyl or lower alkyl fluoroalkyl;

with the proviso that R 0 and R 6 are not each hydrogen and pharmaceutically acceptable salts thereof; these compounds are useful in the treatment of a mammal in a diseased condition such as potassium channel activators or

It can be alleviated by treatment with 5-lipoxygenase inhibitors.

The present invention further provides a compound of formula (I)

And to pharmaceutical compositions containing an effective amount of the compounds or pharmaceutically acceptable salts thereof together with one or more pharmaceutically acceptable non-toxic carriers.

Yet another object of the present invention is to provide a method of treating a mammal having a disease state which has the formula (I), e.g.

It can be alleviated by treatment with compounds that inhibit 5-lipoxygenase, particularly hypertension or asthma. The method comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a mammal in need of such treatment.

As used herein, alkyl means a branched or unbranched saturated hydrocarbon chain having from 1 to 8 carbon atoms, such as methyl, ethyl, propyl, tert-butyl, n-hexyl or n-octyl.

Unless otherwise specified, lower C 1 -C 6 alkyl is a straight or branched saturated hydrocarbon chain such as methyl, ethyl, propyl, isopropyl, tert-butyl, butyl or n-hexyl.

The lower alkoxy group is -O- (lower alkyl) wherein the lower alkyl group is as defined above.

Cycloalkyl is a C3-C8 saturated monovalent monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Halogen means fluorine, chlorine, bromine or iodine.

-5A lower hydroxyalkyl) x lower alkyl substituted with hydroxy as defined above, such as hydroxymethyl, 2-hydroxyethyl or 6-hydroxyhexyl.

A lower fluorine alkyl group refers to a lower alkyl group as defined above substituted with one or more fluorine atoms, such as fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, pentafluoro ethyl or 6-fluorohexyl.

The phenyl group includes all possible isomers of the phenyl group which may be mono- or di-substituted optionally with lower alkyl, lower alkoxy, hydroxy, trifluoromethyl or halogen.

The phenyl (lower) alkyl group is a lower alkyl group as defined above to which the phenyl group is attached, such as benzyl or 1-phenylethyl.

The inert organic solvent or inert solvent under the reaction conditions mentioned is, for example, benzene, toluene, acetonitrile, tetrahydrofuran, dimethylformamide, chloroform, methylene chloride, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane or pyridine. Unless otherwise specified, the solvents used in the reactions of the present invention are inert.

is a group of formula (a), (b) or (c), i.e. R 1 H is 2-oxo-1,2-dihydropyridine, 2-oxopyrrolidine

-6 or 1-oxoisoindoline. Those skilled in the art will recognize that the pyridine, pyrrolidine and isoindoline ring systems may be substituted in various ways, for example, they may contain lower alkyl, lower alkoxy, halogen, and the like, without departing from the spirit and scope of the invention.

The definition of pharmaceutically acceptable salts refers to those salts which retain the biological effectiveness and properties of the compound of formula I and which are not biologically or otherwise disadvantageous. Acid addition salts may be formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and the like, and organic acids such as acetic, propionic, glycolic, tartaric, oxalic, malic, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In addition, compounds of formula (I) wherein R @ ^{2 is} hydroxy and R @ -C (O) R @ ² may also form addition bases. These salts are prepared with inorganic or organic bases. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron (II), zinc, copper, manganese (II), aluminum, iron (III) and manganese (III) salts. Preferred inorganic salts are the ammonium, sodium, potassium, calcium and magnesium salts. Salts with organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines and cyclic amines such as isopropylamine, trimethylamine, diethylamine, triethylamine. , tripropylamine, ethanolamine, 2- (dimethylamino) ethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, beta, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine and N-ethyl piperidine. Preferred organic bases are isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine and choline.

Compounds of the invention wherein R @ 3, X @ 7 X

R 0 and R are eltero, have an asymmetric center and can thus be prepared as a racemic mixture or as individual stereoisomers. For example, each of the stereoisomers may be resolved by resolution of a racemic or non-racemic mixture or a compound of formula (I) obtained in the appropriate step of the synthesis. Of course, individual stereoisomers as well as racemic and non-racemic mixtures of stereoisomers are within the scope of the present invention.

As used herein, the term means that the event or circumstance described below occurs or does not occur, and that the description includes instances in which the above event or circumstance occurs and non-occurrence. For example, the term optionally substituted phenyl means that the phenyl group may be unsubstituted or substituted, and includes both unsubstituted and substituted phenyl groups; optionally converting the free base into an acid addition salt of the acid-8 ··· * ♦ 4 ···· · · · · · · · · · · · · · · · · · · · · · · · · · or not, and the invention includes processes in which the free base is converted into an acid addition salt and those in which this conversion is not carried out.

The term mammal includes humans and all domestic and wild animals without limitation, such as cattle, horses, pigs, sheep, goats, dogs, cats, rabbits, and the like.

The term "treatment" refers to any treatment of a mammal, particularly a human, including

(i) in a subject at risk but not yet diagnosed, preventing the onset of the disease;

(ii) inhibiting the disease, i.e., arresting its development; or (iii) releasing disease, that is to say, causing the disease to recur.

As used herein, a patient condition that can be ameliorated by a potassium channel activator refers to any patient condition generally known in the art to be effectively treated with a potassium channel activator, and to those disease states for which it has been found that the special potassium channel activators can be effectively treated with the compounds of formula (I). Such conditions include, but are not limited to, essential hypertension, hypertension, congestive heart failure, and the like.

-9angina, peripheral vascular obstruction, smooth muscle spasms, especially cerebral spasms, cardiac arrhythmias, seizures, respiratory disorders such as reversible airway obstruction and asthma. The compounds of the present invention are also useful in the treatment of disorders of the gastrointestinal tract, the uterus, or the urinary tract, including ureteric smooth muscle contraction, and glaucoma, epilepsy, psycho-depressive states, and baldness.

A condition that can be ameliorated by treatment with a 5-lipoxygenase inhibitor includes any condition that is generally known in the art to be successfully treated with a 5-lipoxygenase inhibitor. Such conditions include, but are not limited to, pain, inflammatory and allergic conditions, overgrowth, ulcerative colitis and seizure.

A therapeutically effective amount is an amount of a compound of formula (I) that, when administered to a mammal in need thereof, is sufficient to exert an effect on the disease states treated by the compounds of formula (I) mentioned above. The therapeutically effective amount will depend upon the compound, the condition and the severity of the condition, and the mammal being treated, but may be routinely determined by one of ordinary skill in the art and herein.

The numbering system used to name the intermediates and compounds of the present invention as final products is represented by Formula (I).

A compound of formula (I) wherein R 1 and R ² are both methyl, R ^{3 is} nitro, R 2 -oxo-1, 2 to 10 · c ·· * * · · · · · · · · The dihydropyridin-1-yl group, R @ 4 and R @ 2 are both hydrogen, R @ ⁸ hydroxy and R @ ⁸ methyl are designated as follows:

6-nitro-2,2-dimethyl-3- (N-methyl-N-hydroxyaminomethyl) 4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran.

A compound of formula (I) wherein R 2 is methyl, R ^{8 is} trifluoromethyl, 1-oxoisoindolin-2-yl, R ⁴ and R ⁷ are both hydrogen, R ^{8 is} hydrogen, and R ^{8 is} hydrogen. C (O) R ^ 2 wherein methyl is referred to as:

6- (trifluoromethyl) -2,2-dimethyl-3- (acetamidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran.

R 2 and R 2 are each methyl, R ⁸ is pentafluoroethyl, 2-oxo-1,2-dihydro-β-pyridin-1-yl, R 0 and R 6 are each hydrogen, R ⁸ is hydroxy, and R ⁸ is hydrogen. ^The name of the compound containing ⁸ where -C (O) R ^ 2 (in which methyl is) is:

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran.

A preferred class of compounds of the present invention are those wherein R 1 is both methyl and R 2 and R 2 are both hydrogen. A preferred group of these are those derivatives wherein R

1,2-dihydropyridine-l-yl. Preferred subgroups of this group include those wherein R 0 is nitro or trifluoromethyl, R ⁸ is hydrogen, and R ⁸ is -C (O) R 12. Another preferred subgroup is the compound which is · · ·

In QQ, R is hydroxy and R is hydrogen, lower alkyl or a group of the general formula, especially those wherein R 1 is hydrogen, methyl or trifluoromethyl. A third preferred subgroup within this group are those compounds wherein R @ 4 is lower alkoxy and R @ 1 is hydrogen. A fourth subgroup, wherein R is a bromine or chlorine atom, p qq 1, Rc is OH, R ^{XA in} place -COR radical, in particular methyl or R ^ is ethyl containing.

In a second preferred group of compounds are those wherein R ⁴ of 2-oxo-pyrrolidin-l-yl. Within this preferred subgroup are those compounds wherein R @ 3 is hydrogen or hydroxy and R @ 1 is hydrogen, lower alkyl or -C (O) R @ 2.

A third preferred group comprises those wherein R ^{4 is} 1-oxoisoindolin-2-yl. Within this group, a preferred subgroup is those compounds wherein R 8 is hydrogen or hydroxy and hydrogen, lower alkyl or -C (O). ) A radical of formula R

Currently, the following compounds are preferred:

6-nitro-2,2-dimethyl-3- (methoxyamino) methyl-4- (2-oxo-

1,2-dihydropyridine-l-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (formamido) methyl-4- (2-oxo-2dihidropiridin-l-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (acetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

• · · ·

-126-nitro-2,2-dimethyl-3- (trifluoroacetamido) methyl-4- (2-oxo-1,2-dihydropyridin-l-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (hydroxyamino) methyl-4- (2-oxo-

1,2-dihydropyridine-l-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (N-acetamidomethyl) -4- (2-oxo-1,2-dihydropyridine-l-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (N-hydroxyacetamido) methyl-4- (2-oxo-1,2-dihydropyridine-l-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (formamido) -4 (2-oxo-1,2-dihydropyridine-l-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (acetamidomethyl) -4- (2-oxo-1,2-dihydropyridine-l-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (trifluoroacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6-bromo-2,2-dimethyl-3- (N-hydroxyacetamido) methyl-4- (2-oxo-1,2-dihydropyridine-l-yl) -2H-l-benzopyran;

6-chloro-2,2-dimethyl-3- (N-hydroxyacetamido) methyl-4- (2-oxo-1,2-dihydropyridine-l-yl) -2H-l-benzopyran;

6-bromo-2,2-dimethyl-3- (Nrhidroxi propionamido methyl) 4- (2-oxo-1,2-dihydropyridine-l-yl) -2H-l-benzopyran.

Preparation of compounds of formulas 14 and 15

Compounds of formula (I) are prepared from intermediates (14) and (15) and are illustrated in Schemes [I] and [II].

-13Αζ [I] Scheme shows how to derive the different groups R ^ú the benzopyran nucleus in the formulas, Z is lower alkyl, fluoroalkyl group and M is sodium or potassium.

Preparation of compounds of formula (3)

Compounds of formula (1) are commercially available, inter alia, from Aldrich Chemical Company, or in the chemical literature, such as Zalkow and Ghosal, J. Med. Org. Chem. 34, 1646-1650 (1969)] or Martin et al

Betoux [Bull. Soc. Chim. French, 46, 2079-2088 (1969)]. Compounds of formula (2) are commercially available.

For the preparation of compounds of formula 3a wherein X is hydrogen and for the preparation of compounds of formula 3b wherein X is halogen, a suitable compound of formula 1 is prepared with 1 to 3 molar equivalents, preferably 1.5 molar equivalents of compound of formula 2 react for approx. 0.2-1 molar equivalent, more preferably approx. 0.5 molar equivalents in the presence of a secondary organic base such as piperidine, morpholine, pyrrolidine and the like, preferably pyrrolidine.

Preferably, the reaction is carried out in an aromatic solvent, such as benzene, toluene, xylene, preferably toluene, for approx. At a temperature between 60 ° C and 100 ° C, preferably at 85 ° C, for approx. 1-6 days »preferably approx. 3 days. When the reaction is substantially complete, the 3,4-dihydrolbenzopyran-4-one derivative of formula (3) is isolated and purified by conventional means, preferably chromatography.

• · · ·

-14 ···· ··· Compounds of formula (4)

Compounds of formula (4) are prepared from compounds of formula (3a) wherein X is hydrogen. Typically, a suitable compound of formula (3a) in concentrated sulfuric acid is ca. Dissolve at 0 ° C and concentrated sulfuric acid and nitric acid for approx. 1: 6 (v / v) was added in excess while maintaining the temperature between 0 and 5 ° C. The reaction is preferably carried out at 5 ° C for 1-8 hours, preferably about 5 hours. We play it for 3 hours. When the reaction is substantially complete, the 6-nitro-3,4-dihydro-1-benzopyran-4-one derivative of formula (4) is isolated and purified by conventional means, preferably by filtration.

Preparation of compounds of formula (5)

The cyano compounds of Formula 5 are prepared from the nitro compounds of Formula 4 by standard literature procedures, for example, by first reducing the nitro group of the compound of Formula 4 to an amino group, then reacting it with nitrite to form a diazo derivative. The compound of formula (5) is obtained.

In general, a compound of formula (4) is reduced to the corresponding amine in the presence of a suitable heterogeneous catalyst, such as alumina-supported rhodium, platinum oxide or preferably palladium-on-carbon. For example, 0.02-0.3 g, preferably about 10 mg / g of compound (4) dissolved in an inert solvent, preferably methanol, is used. 0.1 g of 10% palladium on carbon was added and the mixture was stirred for ca. 1-5 atmospheres, preferably approx.

hydrogenated at atmospheric pressure. The reaction was allowed to proceed for approx. 20 to 60 ° C, preferably about 20 ° C. The reaction is carried out at a temperature of 40 to 50 ° C until hydrogen uptake ceases, typically about 20 ° C. It takes 4-6 hours.

When the reaction is substantially complete, the amine product is isolated in the usual manner, dissolved in a water-miscible inert solvent, preferably ethanol, and added to an excess of an aqueous acidic solution such as aqueous sulfuric acid or preferably aqueous hydrochloric acid (ca. . 1-2 molar equivalents, preferably ca. 1.1 molar equivalents of alkali metal nitrite, preferably sodium nitrite. The reaction was allowed to proceed for approx. At a temperature of -5 ° C to 0 ° C, preferably about 5 ° C to about 5 ° C. At 0 ° C, ca. Run for 15 minutes.

The diazo compound thus prepared is reacted with cyanide anions in aqueous solution. This aqueous solution is preferably ca. 5-20 molar equivalents, preferably approx. It contains 9 molar equivalents of potassium cyanide together with a similar number of molar equivalents of copper (I) cyanide. The reaction was allowed to proceed for approx. At a temperature of from 50 to 100 ° C, preferably from about 50 ° C to about 100 ° C. 90 ° C, ca. We do this for 1 hour. When the reaction is substantially complete, the 6-cyano-3,4-dihydro-1-benzopyran-4-one derivative (5) is isolated and purified by conventional means, preferably chromatography.

Preparation of compounds of formula (6)

The compounds of formula (3a), (3b), (4) or (5) are then reduced to compounds of formula (6) in which Y is hydrogen, halogen, nitro or cyano, with a suitable reducing agent such as lithium borohydride, lithium. -tri (tert-butoxy) aluminum hydrides, ···· · ··

Sodium borohydride, preferably sodium borohydride, is used. Generally, a compound of Formula (3a), (3b), (4) or (5) is dissolved or suspended in a protic solvent, preferably methanol, and then ca. 1 molar equivalent of sodium borohydride. The reaction was allowed to proceed for approx. At a temperature of from 15 ° C to 30 ° C, preferably from about 15 ° C to about 30 ° C. At 25 ° C, ca. For 30 minutes to 6 hours, preferably approx. 2 hours. When the reaction is substantially complete, the 6-unsubstituted, 6-halo, 6-nitro or 6-cyano-4-hydroxy-3,4-dihydro-1-benzopyran derivative of formula (6) wherein Y is hydrogen or halogen, nitro or cyano, separated and purified by conventional means.

Preparation of compounds of formulas 7a, 7b, 7c and 7d

A compound of Formula 6 wherein Y is hydrogen or halogen, nitro or cyano is then reacted with ca. 0.05 to 0.5 molar equivalents, preferably ca. It is dehydrated in the presence of 0.1 molar equivalent of an acidic catalyst, for example naphthalenesulfonic acid, preferably ptoluenesulfonic acid. The reaction is carried out in a suitable solvent such as benzene or preferably toluene for about 10 minutes. 6-32, preferably approx. It is heated to reflux for 18 hours while the water is removed. When the reaction is substantially complete, the 6-unsubstituted, 6-halo, 6-nitro or 6-cyano-1-benzopyran derivative of formula (7) wherein Y is hydrogen (7a), halo (7b), nitro (7c) or cyano group (7d), is isolated and purified in the usual manner.

Preparation of Compounds of Formula (9) • · ···· · ··

Compounds of formula -17Α (8) are commercially available, for example, from Interchim or may be prepared by the method described by Laganis and Chenard (Tetrahedron Letters, 25 (51), 5831-5834 (1984)).

Compounds of formula (9) are those wherein Z is lower-fluoroalkyl; they are prepared from compounds of formula 7b wherein Y is halogen. A suitable compound of formula 7b is ca. 1.5 to 5 molar equivalents, preferably ca. 3 molar equivalents of compound (8) wherein M is sodium or preferably potassium and Z is lower fluoroalkyl. The reaction was allowed to proceed for approx. 1-4 molar equivalents, preferably approx. The reaction is carried out in the presence of 2 molar equivalents of copper (I) halide, preferably copper (I) iodide, in an inert solvent consisting of a polar solvent, preferably dimethylformamide, and an aromatic solvent, preferably toluene. The reaction is carried out at a temperature high enough to distill the aromatic solvent and continue the distillation until the reaction temperature reaches ca. 130-170 ° C, preferably a

140 ° C and then heated at this temperature for a further 2-10 hours, preferably 4 hours. When the reaction is substantially complete, the 6- (fluoro-lower alkyl) -1-benzopyran derivative of formula (9) is isolated and purified by conventional means, preferably chromatography.

Alternative processes for the preparation of compounds of formulas 7 and 9

Alternatively, intermediates of formula (7) and (9) may be prepared according to Scheme [1 '].

·· ····

Preparation of -18 (b)

Compounds of formula (a) are commercially available, for example, from Aldrich Chemical Company. Compounds of formula (b) may be prepared from compounds of formula (a) by converting an alcohol to a brominated compound, for example, by reacting the alcohol with a brominating agent such as phosphorus tribromide. The reaction may be carried out in the absence of a solvent or in a solvent such as dichloromethane, toluene at a temperature of -10 ° C to 20 ° C, preferably 5 ° C. When the reaction is substantially complete, the alpha-bromopropanone derivative (b) is isolated and purified in a conventional manner.

Preparation of compounds of formula (d)

Compounds of formula (c) are available from Aldrich. Compounds of formula (d) wherein Y is bromo are also commercially available. Compounds of formula (d) wherein X is hydrogen, halogen or nitro may be prepared by reacting a compound of formula (c) in a suitable solvent at a temperature of -5 ° C to 80 ° C with a reducing agent for 1 to 5 hours. for example, reducing a compound of formula (c) with borane-tetrahydrofuran complex in anhydrous tetrahydrofuran at 66 ° C for 2 hours. When the reaction is substantially complete, the 2-hydroxybenzyl alcohol derivative of formula (d) is isolated and purified by conventional techniques.

Preparation of compounds of formula (e)

Compounds of formula (e) are compounds of formula (d) in the form of a base such as potassium carbonate.

-19 ···· · ·· ··, · ·

in an inert solvent such as acetone, ethanol, preferably methyl ethyl ketone. The reaction is carried out at a temperature of 60 to 90 ° C, preferably 80 ° C.

When the reaction is substantially complete, the 3 - [(2-hydroxymethyl) phenoxy] -2-propanone derivative of formula (e) is isolated and purified in a conventional manner.

Preparation of compounds of formula (f)

Compounds of formula (f) may be obtained by reacting compounds of formula (e) with triphenylphosphine hydrobromide in an inert solvent such as toluene, preferably acetonitrile. The reaction is carried out at a temperature of 80 to 100 ° C, preferably 90 ° C, for 1.5 to 4 hours, preferably 2-3 hours. When the reaction is substantially complete, the benzyl triphenylphosphonium bromide derivative of formula (f) is isolated and purified by conventional techniques.

Preparation of compounds of formula (7)

Compounds of formula (7) may be prepared from compounds of formula (f) by reaction with a strong base, such as an alkali metal alkoxide, which is prepared in situ from an alkali metal and an absolute alcohol, preferably sodium and ethanol. The reaction is carried out at a temperature of 0 ° C to 30 ° C, preferably 25 ° C for a period of 9 to 20 hours, preferably 12 hours. When the reaction is substantially complete, the 6-unsubstituted or 6-substituted 1-benzopyran derivative of formula (7), wherein Y is hydrogen (7a), halogen (7b) or nitro

-20 ·· * · · ·· «« ·

The compound of formula (7c) is isolated and purified in the usual manner.

Preparation of compounds of formula (9)

Compounds of formula (9) are prepared from compounds of formula (7b) as described in the preceding paragraph.

Schemes [I] and [I '] illustrate the preparation of intermediates of formula (7a), (7b), (7c), (7d) and (9). Scheme [II] illustrates the conversion of these intermediates to intermediates (14) and (15), wherein R 0 is hydrogen, halogen, lower-carbon fluoroalkyl, cyano or nitro, and R ⁴ 2-oxo-1,2-dihydropyridin-1-yl, 1-oxo-pyrrolidin-1-yl or 1-oxo-isoindolin-2-yl.

Preparation of compounds of formula (10)

A suitable compound of formula (7a), (7b), (7c), (7d) or (9) is prepared for the preparation of compounds of formula (10) wherein r3 is hydrogen, halogen, lower-carbon fluoroalkyl, cyano or nitro. approx. 1-1.8 molar equivalents, preferably ca. 1.2 molar equivalents of epoxidizing agent, for example m-chloroperbenzoic acid. The reaction is carried out in an inert solvent, preferably dichloromethane, at a temperature between 0 ° C and 30 ° C, preferably at 25 ° C, for about 10 minutes. 6 to 48 hours, preferably 18 hours. When the reaction is substantially complete, the 3,4-epoxy-1-benzopyran derivative (10) is isolated and purified in a conventional manner.

* 444 • · ·· «4

Preparation of compounds of formula (12)

Compounds of formula (12) may be prepared so that compounds of formula (10) are ca.

vivalent, preferably ca. 2 molar equivalents of the appropriate compound of formula (11) (available from Aldrich Chemical Company) are represented by R 1 H 2 -oxo-1,2-dihydropyridine, 2-oxopyrrolidine or 1-oxoisoindoline. The reaction is carried out in the presence of a catalytic amount of a strong quaternary organic base, preferably Triton B, in an inert solvent, preferably dioxane, for approx. at the temperature corresponding to the boiling point of the solvent, for approx. 6-48, preferably approx.

for an hour. Once the reaction is substantially complete, the 4-heterocyclyl-3,4-dihydro-

The 3-hydroxy-1-benzopyran derivative is isolated and purified in the usual manner.

Preparation of compounds of formula (13)

A compound of formula (12) is then ca. 1-1.5 molar equivalents, preferably approx. It is dehydrated by treatment with 1 molar equivalent of an alkali metal hydride, preferably sodium hydride. The reaction is carried out under reflux in a suitable ether-type solvent such as diethyl ether, dioxane or preferably tetrahydrofuran. 6-32, preferably approx. Run for 16 hours. When the reaction is substantially complete, the 4-heterocyclyl-1-benzopyran derivative (13) is isolated and purified by conventional techniques.

Preparation of compounds of formula (14)

A compound of formula (13) is ca. 1 molar equivalent of N-bromophthalimide or preferably N-bromosuccinimide in the presence of a catalytic amount of benzoyl peroxide

-22zunk. The reaction is carried out by reacting the components in an inert solvent such as dichloromethane, chloroform or, preferably, carbon tetrachloride for approx. 6-32, preferably approx. Boil for 17 hours. When the reaction is substantially complete, the 4-heterocyclyl-3- (bromoalkyl) -1-benzopyran derivative of formula (14) is isolated and purified by conventional means, preferably chromatography.

Alternative process for the preparation of compounds of formula (14)

Compounds of general formula (14) may also be prepared according to Scheme [II ']. The precursor of formula (g) containing a hydrogen or halogen atom and its preparation is disclosed in European Patent 410,208, which is hereby incorporated by reference. Compounds of formula (g) wherein the nitro or cyano group is present may also be prepared according to the process described in European Patent 410,208.

Compounds of formula (14) wherein R 0 is hydrogen, halogen, cyano or nitro are prepared according to Scheme [II '] in the usual manner starting from the corresponding compounds of formula (g) as the alkyl bromides. from appropriate alcohols. The compound of formula (g) may be reacted with a brominating agent in an inert solvent such as chloroform, dichloromethane or toluene at a temperature of 0 ° C to 110 ° C, for example phosphorus tribromide in toluene at 110 ° C. The reaction may take from 1 to 10 hours, preferably 2 hours, to complete the reaction. Once the reaction is substantially complete, the formula 14 ··· «· 4 ·« «44 * * · · · · · · · ·

The 4-heterocyclyl-3- (bromoalkyl) -1-benzopyran derivative is isolated and purified by conventional means.

Preparation of compounds of formula (15)

In the compound of formula (14), the bromine atom may be replaced by an amino group, i.e., the compound of formula (15) may be obtained by treatment with excess ammonium hydroxide. The reaction is carried out in a protic solvent such as methanol, propanol or preferably ethanol for about 10 minutes. 1-10, preferably approx. 4 hours. When the reaction is substantially complete, the 4-heterocyclyl-3-aminoalkyl-1-benzopyran derivative (15) is isolated and purified by conventional techniques such as crystallization.

Compounds of formula (I)

Compounds of formula (I) may be prepared from intermediates of formulas (14) and (15).

Preparation of (I) compounds wherein R8 is lower alkyl, hydroxy, lower alkoxy, lower alkyl or hydroxyalkyl and R ⁹ is hydrogen, lower alkyl or lower alkyl hydroxyalkyl

For the sake of simplicity, compounds containing R ³ lower alkyl, hydroxy, lower alkoxy or lower hydroxyalkyl groups and R ^{9 being} hydrogen, low saturated alkyl or lower hydroxyalkyl groups can be divided into two groups, i.e. R ⁹ on hydrogen and R ⁹ on lower alkyl or lower hydroxyalkyl ·· * ·

-24tartalmazókra.

a) Compounds of formula I wherein ΙΙθ is lower alkyl, hydroxy, lower alkoxy or lower hydroxyalkyl, and R 1 is hydrogen are prepared from compounds of formula 14 according to Scheme [III]. live. Such compounds are used as starting materials in the preparation of other compounds of formula (I), for example according to Scheme [IV], and therefore, to be clearly distinguished, they are represented by formula (IA). Their production is something

Q is a reaction of a compound of formula (14) with an amine of formula R 0 NH 2 wherein R 0 is lower alkyl, hydroxy, lower alkoxy or lower hydroxyalkyl.

b) Compounds of formula (I) wherein r8 is lower alkyl, hydroxy, lower alkoxy or lower hydroxyalkyl and lower alkyl or lower hydroxyalkyl are also represented by formula (14). Compounds of formula (III) may be prepared by reaction with an amine of formula R 1 -R 4 NH where R 0 is lower alkyl, hydroxy, lower alkanoyl or lower hydroxyalkyl and R 4 lower alkyl or lower hydroxyalkyl.

Compounds of formula (I) or (IA) wherein R < 4 > is lower alkyl, hydroxy, lower alkoxy or lower hydroxyalkyl and R < ⁹ > are hydrogen, lower alkyl, or lower hydroxyalkyl. One way to prepare a compound of formula (14) is by ca. 1-4 molar equivalents, preferably approx. 1.1 molar equivalents of the appropriate amine of formula HNR ⁸ R ⁹ such as methylamine, dimethylamine, 2-hydroxyethylamine). The reaction is carried out in a protic solvent, preferably methanol, optionally in the presence of water, for approx. At a temperature of 0 ° C to 30 ° C, preferably about 10 ° C to about 30 ° C. At 25 ° C, ca. 1-10, preferably approx. Run for 4 hours. When the reaction is substantially complete, the 4-heterocyclyl-3- (substituted aminoalkyl) -1-benzopyran derivative of formula (I) or (IA) is isolated and purified by conventional means, preferably by crystallization. wherein R 0 is lower alkyl or lower hydroxyalkyl and R ^{9 is} hydrogen, lower alkyl or lower hydroxyalkyl.

Alternatively, a compound of formula (14) may be prepared in an amount of about 10 minutes. 1 molar equivalent of the appropriate amine of formula HNR ⁸ R ^{9 in a} protic solvent, preferably ethanol, for approx. at the boiling point of the solvent, ca. For 5 minutes to 2 hours, preferably approx. Reaction was continued for 30 minutes. After the reaction is substantially complete, the 4-heterocyclyl-3- (substituted aminoalkyl) -1-benzopyran derivative of formula (I) or (IA) is isolated and purified by conventional methods, preferably by crystallization. The use of this method is advantageous when R ⁸ · · · ·

-26hydroxy or lower alkoxy; and R ^{8 is} hydrogen or lower alkyl.

Preparation of compounds of formula I wherein R ^{8 is} hydrogen, lower alkyl, lower alkoxy, hydroxy or lower hydroxyalkyl, and R ^{8 is} -SOqR ^, -COqR ^ ⁸ , -C (O) NR ¹¹ R ^12. , -C (S) NRÜr1 _va ² g _y-C (O) ^R12 group of formula

Compounds of formula I wherein:

^R8 is hydrogen, lower alkyl, lower alkoxy, hydroxy or lower alkyl, hydroxy-alkyl and ^R8 -SO2R ^ ^8,

-C (S) NR ¹¹ R ¹² or -C (O) R ¹² , wherein R 4, R ⁸ and R ¹² are as defined in Scheme [IV] above. In the formulas, R ⁸ is as defined above and R ^{8 is} -SO ² R ¹⁰ , -CO ² R ¹⁰ , -C (O) NR ¹¹ R ¹² ,

-C (S) NRÜr1 ² or -C (O) R ² · radical.

A) Compounds of formula (I) wherein R ^{8 is} -C ¹⁰ R ¹² and R ^{2 is} hydrogen

Compounds of general formula (I) in which

R ⁸ is as defined above, and R ^{8 is} -C (O) R ¹² , wherein R ^{12 is} hydrogen, a corresponding general formula (15) or (IA), such that a lower alkyl formate, preferably with a large excess of methyl formate as a solvent at reflux, ca. For 10 hours to 3 days, preferably approx. We react for 27 hours. When the reaction is substantially complete, the 4-heterocyclyl-3 (formamidoalkyl) -1-benzopyran derivatives of formula I wherein

R ⁸

and the formyl group are isolated and purified by conventional methods, preferably by crystallization.

B) Compounds of Formula I wherein R 1 -C (O) r ^{12 is} (1) wherein R ^{2 is} lower alkyl or lower fluoroalkyl

For the preparation of compounds of formula I wherein R @ ³ is as defined above and R @ ² -C (O) R @ ² wherein R @ ^{2 is} lower alkyl or lower alkyl fluoroalkyl, a suitable ) or a compound of formula (IA) for about 10 minutes. 1-2 molar equivalents, preferably 1.2 molar equivalents of an acylating agent, preferably an acid anhydride of the formula R 1 CO ² g wherein R ^{2 is} lower alkyl or lower alkyl fluoroalkyl, from about 1 to 1.5 molar equivalents, preferably ca. .

1.2 molar equivalents in the presence of a tertiary base, preferably triethylamine. The reaction is carried out in an inert solvent, preferably dichloromethane, when R @ 4 is lower alkyl, lower alkoxy or lower hydroxyalkyl, preferably ca. At 25 ° C, and when R @ 3 is hydroxy, preferably ca. 0 ° C. The reaction was allowed to proceed for approx. 1-10, preferably approx. It is carried out for 4 hours when fused to a fluoroalkyl group with a senatentate R and ca. 8 hours at which R is a lower alkyl group. When the reaction is substantially complete, the 4-heterocyclyl-3-amidoalkyl-1-benzopyran derivative of formula (I) wherein R @ 4 is as defined above and R @ 4 -C (O) R @ ⁴² wherein R @ 4 is ¹ ^ low carbon

-28alkyl or low-carbon fluoroalkyl, is isolated and purified by conventional methods, preferably by crystallization.

(2) In which R ^{2 is} lower alkyl

Compounds of formula (I) wherein R (R) is as defined above and R (R) -C (O) R 1 - ² , wherein R 1 - ( ²⁾ lower alkyl may be prepared by reacting B (1) ) starting from a compound of formula (15) or (IA). 1-2 molar equivalents, preferably ca. 1.2 molar equivalents of an acylating agent, preferably an acid halide of the formula R ^ ² COCl or R ^ ² COBr, wherein R ^ ^{2 is a} lower alkyl group, ca. 1-1.5 molar equivalents, preferably approx. 1.2 molar equivalents in the presence of a tertiary base, preferably triethylamine. The reaction is carried out in an inert solvent, preferably dichloromethane, when R @ 4 is lower alkyl, lower alkoxy or lower hydroxyalkyl, preferably at 25 [deg.] C., and when R @ 3 is hydroxy, preferably at about 25 ° C. 0 ° C. The components are approx. 1-10, preferably approx. The reaction was allowed to proceed for 4 hours. When the reaction is substantially complete, the 4-heterocyclyl-3- (alkylamidoalkyl) -1-benzopyrpyran derivative of formula (I) wherein R is as defined above and R ^{a is} -C (O) R ^The group of Formula ² , wherein R 1 is C ² lower alkyl, is isolated and purified by conventional means, preferably by crystallization.

C) Compounds of formula (I) wherein R @ 4 is -COoR ^ θ

Compounds of formula I which are

In -29, ΙΙθ is as defined above, and R 1 -CO ₂ R 10, wherein R 1 -C 6 is lower alkyl, are prepared from the corresponding compound of formula (15) or (IA), which is prepared in approx. 1-2 molar equivalents, preferably ca. 1.2 equivalents C1CO ₂ R ¹⁰ of the formula (lower alkyl) chloroformate -alalkil approx. 1-1.5 molar equivalents, preferably approx.

1.2 molar equivalents in the presence of a tertiary base, preferably triethylamine. The reaction is carried out in an inert solvent, preferably dichloromethane, for about 10 minutes. At a temperature of 0 ° C to 30 ° C, preferably about 10 ° C to about 30 ° C. 2 hours. After the reaction is substantially complete, the general formula (I) is 4-heterocyclic-3- (carbamoyl) alkyl-l-benzopyran derivative, in which R8 is as defined above and -CO ₂ R ® group of the formula, R ^ The lower alkyl group is isolated and purified by conventional means, preferably by crystallization or chromatography.

D) Compounds of formula I wherein -C (O) NrHr12 is a group

Compounds of formula (I) compounds of the formula wherein R8 is as defined above and R® -C (O) NR ^^ R ^ ² Formula 11 12 group, R is hydrogen and R is lower alkyl or lower alkyl fluoroalkyl is prepared by reacting a suitable compound of formula (15) or (IA) with an isocyanate of formula ^Ε1ώ ΝΟΟ, for example ethyl isocyanate. The reaction is carried out in an inert solvent, preferably dichloromethane, for approx. 0 ° C and

At a temperature of 30 ° C, preferably about 30 ° C. At 25 ° C for 1-5 hours, preferably approx. After the reaction is substantially complete, the 4-heterocyclyl-3-30 (ureidoalkyl) -1-benzopyran derivative of formula (I) wherein R @ 4 is as defined above and R @ 4 -C (O). NrHr1 ² radical, preferably hydrogen and R ² is lower alkyl or fluoro-lower alkyl group, and is separated in a customary manner, preferably purified by chromatography.

Compounds of formula (I) wherein R8 is as defined above and R® -C (0) NrHr1 ² group of formula, R ^IX and R ^Lis a transverse hydrogen may also be prepared by reacting a compound (15) or (IA) The compound of formula I is reacted with trialkylsilyl isocyanate, preferably trimethylsilyl isocyanate. The reaction is carried out in an inert solvent, preferably tetrahydrofuran, under a nitrogen atmosphere, for approx. 0 ° C and approx. At a temperature of 30 ° C, preferably about 30 ° C. At 25 ° C, ca. For 10-18 hours, preferably about 10 minutes. 12 hours. When the reaction is substantially complete, the 4-heterocyclyl-3- (ureidoalkyl) -1-benzopyran derivative of formula (I) wherein R is as defined above and R ^{3 is} -C (O) Nr 11r 12, wherein R Both R ² and R ² are hydrogen, separated and purified by conventional means, preferably by chromatography.

In the case where it is desired to produce non-hydrogen containing compounds, a suitable compound of formula (15) or (IA) may also be prepared with a WC (0) NrHr ¹² compound in which W is chlorine or bromine such as dimethyl-. reaction with carbamoyl chloride. The reaction was allowed to proceed for approx. 1-1.5 molar equivalents, preferably approx. 1.2 molar equivalents in the presence of a tertiary base in an inert solvent for approx. 0 ° C to 30 ° C for approx. It is carried out for 1-5 hours.

• · ·

E) Compounds of formula I wherein -C (S) -

For the preparation of compounds of formula (I) wherein R @ 3 is as defined above and -C (S) NR @ 1 - R @ 4 wherein R @ 1 is hydrogen and R @ 2 is lower alkyl or lower alkyl. The reaction is carried out with an isothiocyanate of the formula NCS, such as methyl isothiocyanate. The reaction is carried out in an inert solvent, preferably dichloromethane, for approx. 0 ° C and approx. At a temperature of 30 ° C, preferably about 30 ° C. At 25 ° C, ca.

hours to days, preferably approx. After 26 hours.

After the reaction is substantially complete, the 4-heterocyclyl-3- (thioureidoalkyl) -1-benzopyran of general formula (I), in which hydrogen and R12 lower alkyl or lower fluoroalkyl groups are isolated, is isolated. and purified by conventional means, preferably by chromatography.

Compounds of formula (I) wherein r8 is as defined above and -C (S) N ^^

Alternatively, H 2 may be prepared by reacting a suitable compound of formula (15) or (IA) with trialkylsilyl isothiocyanate, preferably trimethylsilyl isothiocyanate. The reaction is carried out in an inert solvent, preferably tetrahydrofuran, for approx.

0 ° C and approx. 30 ° C, preferably about 25 ° C, for approx. For 1 to 4 hours, preferably approx. 2 hours. When the reaction is substantially complete, the formula I · · · · ·

4-heterocyclyl-3- (thioureidoalkyl) -1-benzopyran, wherein R 1 is as defined above and R 1 -C (S) NR 1 - ² R ² -, where R is hydrogen and R ¹ -. is also hydrogen, isolated and purified in the usual manner.

In the case when we want to obtain compounds containing no hydrogen rH place, it is also possible that a proper (15) or (IA) is reacted with a toilet (S) NR ^^ R ^ · ² compound of formula wherein W chlorine or bromine. The reaction was allowed to proceed for approx. 1-1.5 molar equivalents, preferably approx. 1.2 molar equivalents in the presence of a tertiary base in an inert solvent for approx. 0 ° C to 30 ° C for approx. It is carried out for 1-5 hours.

F) Compounds of Formula I wherein R 1 -SC 6 R 1 -O

Compounds of formula (I) wherein R @ 4 is as defined above and Ηθ-SO2 R @ 4 wherein R @ 4 is lower alkyl may be prepared by reacting a suitable compound of formula (15) or (IA) . 1 to 1.5 molar equivalents, preferably 1 molar equivalent of lower alkylsulfonyl halide of the formula R 10 SO 2 Cl or R 1 SO 2 Br. The reaction is carried out in an amount of 1 to 1.5 molar equivalents, preferably ca. 1.1 molar equivalents of a tertiary base, preferably in the presence of triethylamine, in an inert solvent, preferably dichloromethane, ca. At a temperature of 0 ° C to 30 ° C, preferably about 10 ° C to about 30 ° C. At 25 ° C for approx. For 1 to 10 hours, preferably about 10 minutes. Run for 4 hours. When the reaction is substantially complete, the 4-heterociklil3- formula (sulfonamido alki1) -1-benzopyran derivative (I) as defined above and wherein R® R§ _-SO2 R radical,

In particular, R 1 -C 6 is lower carbon, is isolated and purified in the usual manner.

Alternative process for the preparation of compounds of formula (I)

Schemes [I] to [IV] illustrate the preparation of compounds of formula (I), which first comprises the preparation of compounds (7) and (9), which are converted to the 3,4-epoxy derivatives of formula (10), then reacting the R ⁴ group with the R ⁴ H moiety at the 4 position, dehydrating the resulting 3,4-dihydro compounds 12 to the benzopyrans 13 and then selectively brominating the 3-alkyl moiety. The bromo derivative (14) thus obtained can be converted into various compounds of formula (I).

Obviously, reversing the reaction steps yields the same result. That is, the substituted compounds of formulas (7) and (9) can first be brominated to compounds of formula (16), which can then be converted to compounds of formula (I) by analogy to the procedures outlined in Schemes [II], [III] and [IV]. as shown in Scheme [V].

The reaction of each step of Scheme [V] is carried out in a manner similar to that of Scheme [II], [III] and [IV]. For example, the first step in Scheme [V] is the bromination of the 3-alkyl group to give a compound of formula (16). The reaction conditions correspond to those used in Step 4 of Scheme [II]. The bromine atom of the compound of formula (16) is -NR R

The conversion of the group to a group of the compounds of formula (III) can be carried out according to the procedures of Schemes [III] and [IV]. The second step in Scheme [V] is the epoxidation of a double bond. The reaction conditions are similar to those used in Step 1 of Scheme [II].

It should be noted that the 3-hydroxy compound (19) formed by reaction of 18 with 2-oxopyrrolidine or 1-oxoisoindoline is spontaneously dehydrated to give the desired alkali metal hydride. no treatment is required. However, the reaction of the compound of formula (18) with the 3-hydroxy derivative of formula (19) resulting from the reaction of 2-oxo-1,2-dihydropyridine is stable and dehydration according to Scheme [II] must be performed.

It is also suggested that in the case of a compound of formula 17 wherein R @ 3 is a hydroxy group, that is, R? -ΝΗθΗθ, the hydroxy group must first be protected, for example, converted to a benzyl ether, benzoyl derivative, tetrahydropyranyl ether or the like, by methods well known to those skilled in the art. This protecting group is then removed in the final step.

Purification of compounds of formula (I) and intermediates

Isolation and purification of said compounds and intermediates, if desired, by any suitable separation or purification process, such as filtration, extraction, crystallization, column chromatography, thin layer chromatography, thin layer chromatography, ":" '. ·· · .. * · ·.; ·:.

·· ··. ·.

-35, preparative, low or high performance liquid chromatography, or a combination thereof. For a more detailed description of suitable separation and isolation procedures, reference is made to the following examples. However, other equivalent separation and isolation procedures may also be employed.

The products in salt form can also be isolated in the usual manner. For example, the reaction mixture is evaporated to dryness and the salts can be purified by conventional methods as listed above.

Salts of the compounds of the formula I are acid addition salts

The compounds of formula (I) may be converted into the corresponding acid addition salts. The conversion is effected by treatment with at least a stoichiometric amount of the appropriate acid such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and organic acids such as acetic, propionic, glycolic, pyruvic, oxalic, malic, tartaric, , maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, lower acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid. Typically, the free base is dissolved in an inert organic solvent, such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol, and the acid is added in a solution in the same solvent. The temperature is maintained between 0 ° C and 50 ° C. The acid formed precipitates spontaneously or after adding a less polar solvent.

The acid addition salts of the compounds of formula I are a

-36 can be converted to the corresponding free base by treatment with at least stoichiometric amounts of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate or ammonia.

Base addition salts

Compounds of the present invention wherein R @ 3 is hydroxy and -C (O) R @ 2 may form base addition salts which may be prepared with inorganic or organic bases. Salts with inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron (II), zinc, copper, manganese (II), aluminum. , iron (III) and manganese (III) salts. Preferred inorganic salts are the ammonium, sodium, potassium, calcium and magnesium salts. Salts with organic bases include, but are not limited to, primary, secondary and tertiary amines, substituted amines such as naturally occurring substituted amines and cyclic amines such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, Nalkylglucamines, theobromine, purines, piperazine, piperidine, N-ethyl piperidine. Preferred organic bases are isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine and choline. Typically, we proceed in such a way that (I)

Compound Q wherein R 0 is hydroxy and -C (O) r 12 is in an inert organic solvent such as diethyl ether, ethyl acetate, chlorine: ···:

It is dissolved in ···· form, ethanol or methanol and the base is dissolved in a suitable solvent. The temperature is maintained between 0 ° C and 50 ° C. The resulting salt precipitates after addition of either spontaneous or less polar solvent.

in summary, the compounds of the present invention are prepared by the following processes:

A process for the preparation of a compound of the formula I in which

R ^X and R ² are each independently hydrogen or lower alkyl, or together with the carbon to which they are attached form a C 3 -C 8 cycloalkyl;

R is hydrogen, halo, lower fluoroalkyl, cyano or nitro; a group of formula (a), (b) or (c);

R5 and ^R8 are independently hydrogen or lower alkyl; and

R? A group of the formula -NR ⁸ R ^{9 in} which

^R8 is lower alkyl; lower alkoxy, hydroxy or lower hydroxyalkyl; and

R ^{9 is} hydrogen, lower alkyl, lower hydroxyalkyl, such that

a) reacting a compound of formula 14 with an amine derivative of formula HNR ⁸ R ⁹ wherein R ⁸ and R ⁹ are as defined above; obsession

b) reacting a free base of formula (I) with an acid such as a pharmaceutically acceptable acid addition salt * · ♦ * · »·

-38kapunk; obsession

c) reacting the acid addition salt of a compound of formula I with a base to form the corresponding free base; obsession

d) converting the acid addition salt of a compound of formula I into another pharmaceutically acceptable acid addition salt of a compound of formula I.

A process for the preparation of a compound of formula I wherein R ⁴ , R ² , R ³ , R ⁴ , R ⁵ , R ⁸ , R ⁷ and R ⁸ are as defined above, and

R ⁹ C (O) R ⁴² group of formula, R ⁴² is hydrogen, which comprises a (15) or (IA) compound is reacted with a lower alkyl formate.

3. A process for the preparation of compounds of formula I wherein R ⁴ , R ² , R ³ , R ⁴ , R ⁸ , R ⁸ , R ⁷ and R ⁸ are as defined above and

R ^{9 is} -SO ² R ¹⁰ , -CO ² R ¹⁰ , -C (O) NR ¹⁴ R ¹² , -C (S) NR ⁴¹ R ^12, or

9 z z>

A group of the formula -CfOjR ¹ -C ⁴ in which

R ⁴⁸ and R ^{44 are} lower alkyl; and

R ^{42 is} lower alkyl or lower fluoroalkyl;

in which one (15) or (IA), a compound of formula WSO ₂ R ^18, WC02R ¹⁰ WCOR ^12, (R ¹² CO) 2 O, WC (O) NR ⁴¹ R ¹² or

WC (S) NR ⁴⁴ R ⁴² wherein W is chloro or bromo and R ⁴⁸ , R ⁴⁴ and R ⁴² are as defined above.

A process for the preparation of compounds of formula I wherein R ⁴ , R ² , R ³ , R ⁴ , R ⁸ , R ⁸ , R ⁷ and R ^{8 are} as defined above. and

-C (O) NHR12 or -C (S) NHR12, wherein R1 is a lower alkyl group or a lower fluoroalkyl group having one of the formula (15) or (IA). The compound of formula (II) is reacted with a compound of the formula (I) or (R) NCS.

5. A method of preparing wherein R ⁴ ,, R ^4, R 5 _f R6, R7 and R8 are as defined above and R9 is -C (O) NHR ⁴ 2 _v w C (S) NHR ^ 2 (I) compounds of the formula a group of the formula EMI3.1 wherein: R12 is hydrogen;

wherein a compound of formula (15) or (IA) is reacted with trialkylsilyl isocyanate or trialkylsilyl isothiocyanate.

A process for the preparation of a compound of formula (I) wherein R 1, R 4, R ⁴ , R ⁶ , r ⁶ , r ⁷ , r ⁸ and r 9 are as defined above, wherein a compound of formula (19) is an alkali metal. -hydride.

Area and method of application

A) General application

The compounds of the invention exhibit valuable pharmacological properties in mammals, including activating the potassium channel. Consequently, the compounds of the invention have important therapeutic effects on a variety of tissues, including smooth and cardiac muscles. [See. for example, J. Med. Chem. 33: 1529-1541 (1990), Drugs, 4.0, 785 * ········

791 (1990) and Trends in Pharmacological Sciences 11, 417422 (1990).]

For example, the compounds of formula I are able to exert a smoothing action on smooth muscles and are therefore useful in the treatment of mammals in which a smoothing agent is required and are particularly useful in the treatment of essential and pulmonary hypertension, congestive heart failure, angina, peripheral vascular disease, heart and cerebral spasms, smooth muscle cramps and seizures.

These derivatives are also useful in the treatment of disorders associated with the contraction of the gastrointestinal tract, the uterus, and the urinary tract, including the smooth muscle of the ureter. Such disorders include, but are not limited to, hypersensitivity bowel syndrome, premature childbirth pains, menstrual disorders, incontinence, kidney abnormalities, urinary retention, kidney cramps and gallstone disorders.

The compounds of the present invention also have bronchodilator activity and are therefore useful in the treatment of respiratory disorders.

Such disorders include, but are not limited to, reversible airway obstruction and asthma.

As potassium channel activators, the compounds are useful in the treatment of cardiac arrhythmias, myocardial infarction, ischemic heart disease and angina.

The compounds are also useful in the treatment of glaucoma, central nervous system disorders such as epilepsy and psycho-depressive states, and baldness. Other Pathological Disorders Related to Age, Ische

-41mia, inflammation, or edema (e.g., brain), proliferative diseases of an organ or skin, and metabolic diseases associated with obesity and glucose metabolism disorders can be treated or prevented by the compounds of the present invention.

The compounds of formula I have inhibitory activity on 5-lipoxygenase and therefore exhibit important pharmacological properties. [See. for example, Comprehensive Medical Chemistry, 1990, 2, 147-173; Annual Reports in Medical Chemistry, 17. 203-217 (1982); Annual Reports in Medicine Chemistry 24, 61-70 and 71-79 (1990); Advances in Prostaglandin Thromboxane and Leukotriene Research, 2.1, pt a-b, 109-112 (1990); Drugs of the Future 16, 547-558 (1991); Journal of Ocular Pharmacology,

4 (1): 43-49 (1988).]

The compounds of formula (I) are therefore useful in the treatment of pain and inflammatory conditions including rheumatoid arthritis, osteoarthritis, mucositis, sneezing, gout and ocular inflammation (such as hypertension leading to the development of ophthalmic glaucoma).

As inhibitors of 5-lipoxygenase, they are also useful in the treatment of allergic chronic obstructive pulmonary diseases such as asthma, bronchitis, emphysema, pulmonary insufficiency and pulmonary hypertension.

The compounds are also useful in the treatment of tuliporous disorders such as psoriasis.

Compounds of Formula I of the Invention Also Treated for the Treatment of Ulcerative Colitis and Seizures ···· 4

-42 prove useful.

B) Impact assessment

The potassium channel activating property of the compounds of formula (I) may be determined by a variety of in vitro assays known to those skilled in the art; for example, J. Pharm. Exp. Ther. 248: 1261-1268 (1989) or a modified version thereof.

The smooth muscle relaxant properties of the compounds can be determined by in vitro and / or in vivo experiments. For example, the method described by Taylor S.G et al., Brit.J.Pharmacol.94, 853-863 (1988) or a modified version thereof may be used.

The antihypertensive activity of the compounds of the invention may be determined in vivo (as described in Popovic V. and Popovic P., J. Applied Physiol. 15, 727-728 (1960), or a modified version thereof) in alert spontaneously hypertensive rats. with an arterial catheter.

The compounds of formula (I) also exhibit hydrogel-expanding activity. This property in in vivo guinea pigs is described by Dixon W.E. and Brodie T.G. J.Physiol. 29, 97-173 (1903)] or a modified version thereof.

The activity against glaucoma is estimated, for example, by an in vivo rabbit assay (L.D.Waterbury, 1990, Investigative Ophtalmology and Visual Science, 31, 2560-2567) or a modified version thereof.

The compounds of formula (I) also exhibit selective peripheral vasodilator properties which are in vivo

-43 ”· '·» j .... _:

· .. · '.. · · .. · ·''· ⁹ ·· ··· ·· in rats_a Naunyn-Schmiedeberg's Arch. Pharmacol. 3,373,334-346 (1988)].

The compounds of formula (I) also exhibit 5-1 lipoxygenase inhibitory activity, as determined by an in vitro assay in human blood as described in Example 28 and accepted in the art (Radmark et al., Febs Letters, 110 (2). 213-215 (1980)). We measured.

C) General dosage

The compounds of the present invention may be administered in any pharmaceutically acceptable form, either alone or in combination with other pharmaceutically acceptable excipients, in solid, semi-solid, nebulized or spray dosage forms such as tablets, capsules, powders, liquids, suspensions, suppositories, aerosols or or in sustained or controlled release dosage forms, when sustained delivery of a compound at a predetermined rate is desired, preferably in unit dosage form suitable for single dose administration. The formulations generally comprise a conventional pharmaceutical carrier or excipient and a compound of formula (I) or a pharmaceutically acceptable salt thereof. In addition, these compositions include other therapeutic agents, carriers, adjuvants such as antihypertensive agents such as angiotensin converting enzyme (ACE) inhibitors, beta-blocking agents and diuretics; bronchodilators and anti-asthma agents, steroids; anti-inflammatory agents; and non-steroidal anti-inflammatory agents (NSAIDs).

⁹ ·· · * ··

-44 ··· * • · • 9

· 4 «· ·· :. ·.

··· ··

The amount of active compound administered will, of course, depend on the individual and the condition being treated, its severity, the route of administration and the judgment of the prescriber. However, the effective dose is about 10 mg. 0.00003 mg and ca. 20 mg / kg body weight, preferably approx. It is between 0.0003 mg and 2 mg / kg body weight. Generally, for a person weighing 70 kg, this will amount to 0.002-1400 mg / day or preferably 0.02-140 mg / day.

Typical non-toxic solid carriers for solid compositions include, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, talc, cellulose derivatives, glucose, sucrose, magnesium carbonate, polyvinylpyrrolidone, saturated polyglycerolated glycerides, . Liquid pharmaceutical formulations may be prepared, for example, by dissolving or suspending the active ingredient and optionally a pharmaceutical adjuvant in a carrier such as water, saline, aqueous dextrose, glycerol, glycols, ethanol and the like to form a solution or suspension. If desired, the pharmaceutical composition may contain minor amounts of non-toxic excipients, such as wetting, emulsifying or solubilizing agents, pH buffering agents and the like, such as sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolate, triethanol , triethanolamine oleate, etc. It contains. The preparation of such dosage forms is known or obvious to those skilled in the art; ld. for example Remington's Pharmaceutical

-45Sciences (Mack Publishing Company, Easton Pennsylvania, 15th Edition, 1975). In any case, the composition to be administered contains the active ingredient in an amount effective to alleviate the symptoms of the subject being treated.

Dosage forms containing from 0.005 to 95% by weight of the active ingredient, i.e., the compound of formula I or a salt thereof, may be prepared using non-toxic carriers.

A pharmaceutically acceptable non-toxic formulation for oral administration may be formulated with any conventional excipients such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, talc, cellulose derivatives, glucose, sucrose, magnesium carbonate. Such formulations include solutions, suspensions, tablets, capsules, powders, sustained release formulations. These compositions may contain from 0.01 to 95% by weight, preferably from 0.1 to 50% by weight, of the active ingredient.

For the preparation of a solid dosage form, the solution or suspension, for example, in porylene carbonate, vegetable oils or triglycerides is preferably contained in a gelatin capsule. Such diester solutions and their preparation and encapsulation are described in U.S. Patent 4,328,245; U.S. Patent Nos. 4,409,239 and 4,410,545. To form a liquid dosage form, the solution, for example made with polyethylene glycol, is diluted with an appropriate amount of a pharmaceutically acceptable liquid carrier, such as water, to facilitate measurement of the dose to be administered.

-46Liquid or semi-solid oral formulations may also be prepared by dissolving or dispersing the compounds of formula I or salts thereof in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbobate), and diluting or diluting these solutions or suspensions reserved.

Other useful formulations include. Re. U.S. Patent Nos. 28,819 and 4,358,603.

The compositions may be administered in a single unit dose for continuous treatment or, when symptoms are specifically required, at a time as desired, in a single unit dose.

Parenteral formulations are generally injections, which may be subcutaneous, intramuscular or intravenous injection. Injectable dosage forms may be liquid, such as solutions or suspensions, or solid forms which may be reconstituted with a liquid prior to injection, or emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like. In addition, if desired, the pharmaceutical compositions may contain minor amounts of nontoxic excipients, such as wetting or emulsifying agents, pH adjusting agents, solubilizing agents, and the like, such as sodium acetate, sorbitan monolaureate, triethanolamine oleate, or cyclodextrins.

A recently used parenteral dosage form is an implanted slow or sustained release system,

-47 which keeps the dose constant. See, for example, U.S. Patent No. 3,710,795.

The percentage of active ingredient in such parenteral formulations will depend to a large extent on its nature and the potency of the compound and the individual's need. An amount of 0.01% to 10% of active ingredient may be used in the solution and more if the composition is solid and is subsequently diluted according to the above%. The solution in the form of a solution preferably contains from 0.02 to 8% of the active ingredient.

Nasal administration is generally characterized by inhalation of the compound of formula I alone or in combination with other pharmaceutically acceptable excipients.

For the respiratory tract, the compounds of Formula I may be administered in the form of an aerosol or nebulized solution or a finely dispersed powder, either alone or in combination with an inert carrier such as lactose, for the treatment of reversible respiratory tract and asthma. In such cases, the particle size of the composition is less than 50 microns, preferably less than 10 microns.

Pharmaceutical compositions suitable for the treatment of glaucoma may be prepared by admixing the active ingredient with a non-toxic pharmaceutical organic carrier or a pharmaceutically acceptable inorganic carrier. Examples of acceptable carriers for such pharmaceutical compositions are water, water and water-miscible solvents such as low-carbon alcohols or vegetable oils, glycerol, polyalkylene glycols, hydroxyethyl cellulose, ethyl 48 oleate, carboxymethyl cellulose, polyvinylpyrrolidone or the like. water-miscible polymers such as cellulose derivatives (methyl cellulose, carboxymethyl cellulose with base, hydroxymethyl cellulose, hydroxyethyl cellulose) and other conventional acceptable carriers. The pharmaceutical compositions may also contain non-toxic excipients such as emulsifying, preserving, wetting and thickening agents, such as polyethylene glycol 200, 300,

400 and 600; carbówax 1000, 1500, 4000, 6000 and

000, a polyanionic polymer, such as a carboxyvinyl polymer, having ca. 4000 and approx. 6,000,000 molecular weight; antibacterial components, such as quaternary ammonium compounds, phenylmercury salts, which can be used for cold sterilization and which do not cause damage when used; thimerosal, methyl and propyl paraben, benzyl alcohol, phenylethanol; buffering agents and isotonic agents such as alkali metal chloride, borate, acetate, gluconate buffers; antioxidants such as sodium metabisulfite, butylated hydroxyanisole, butylated hydroxytoluene and other conventional components such as sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monopalmitate, dioctyl monosalmitate, diamine tetraacetic acid and the like.

The following reference examples and examples are provided to illustrate the invention and are not intended to limit its scope.

Reference example 1

Preparation of compounds of formula (3)

A) Preparation of compounds of formula 3 wherein X is hydrogen and R ^{2 is} methyl and R * ^{2 is} hydrogen.

A solution of 2-hydroxypropiophenone (500 mL, 3.64 mmol), acetone (400 mL) and pyrrolidine (150 mL, 1.8 mol) in toluene (1000 mL) was heated at 85 ° C for 66 h. The cooled solution was then washed sequentially with water, aqueous hydrochloric acid and aqueous sodium hydroxide. The toluene layer was separated and the solvent removed under reduced pressure. The residue was chromatographed on silica gel using dichloromethane / heptane (50:50, v / v) to give 81 g of 2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one 3a. oil.

¹ H-NMR (CDCl ₃ ): δ 1.3 (d, 3H); 1.4 (s, 3H); 1.6 (s, 3H);

2.5-3.0 (q, 1H); 6.8-8.1 (m, 4H).

B) Preparation of compounds of formula 3 wherein X is bromo and R ^{2 is} methyl and R 1 and H

The procedure of Example 1A above is followed, however

2-Hydroxypropiophenone is replaced with 2-hydroxy-5-bromopropiophenone to give the following compound (3):

6-Bromo-2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one, oil of formula 3b;

¹ H-NMR (CDCl 3): delta 1.2 (d, 3H); 1.3 (s, 3H); 1.5 (s, 3H);

2.7 (q, 1H); 6.8 (d, 1H); 7.5 (d, 1H); 7.9 (s, 1H).

Reference Example 2 Preparation of Compounds of Formula 4

Preparation of compound of formula 4 wherein R ¹ and R ^{2 are} methyl and R ^{8 is} hydrogen (0.426 mol) 2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one 695 ml To a solution of concentrated sulfuric acid at 0 ° C was added a mixture of 30 ml of concentrated sulfuric acid and 175 ml of 65% nitric acid while maintaining the temperature below 5 ° C. The reaction mixture was stirred for 3 hours at 5 ° C, then poured into ice water and the crude product was collected by filtration. The product was dried and washed with diisopropyl ether to give 44 g of 6-nitro-

2,2,3-Trimethyl-3,4-dihydro-2H-1-benzopyran-4-one is obtained, m.p. 78 ° C.

Reference Example 3 Preparation of Compounds of Formula (5)

Preparation of a compound of formula 5 wherein R ^{2 is} methyl and R ⁸ and R ^{8 are} hydrogen

A) 23.5 g (0.1 mol) of 6-nitro-2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one and 2 g of 10% palladium on carbon in methanol under a hydrogen atmosphere. Stir at -50 ° C for 5 hours at ambient pressure. The solution was then filtered and the solvent removed from the filtrate under reduced pressure to give 21 g of 6-amino-2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one as an oil.

B) to a mixture of 293 ml of water and 25.7 ml of concentrated hydrochloric acid at 0 ° C

A solution of 6-amino-2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one (20.5 g, 0.1 mol) in ethanol (140 mL) was added. A solution of sodium nitrite (7.6 g, 0.11 mol) in water (90 ml) was added at such a rate that the temperature

rise above 0 ° C. After 15 minutes at 0 ° C, the mixture was poured into aqueous solution containing 58.6 g (0.90 mol) of potassium cyanide and 80.61 g (0.90 mol) of copper (I) cyanide at 90 ° C. while maintaining the reaction temperature above 70 ° C. The resulting mixture was heated at 90 ° C for 1 hour, cooled to 20 ° C, extracted with ethyl acetate and the extract was washed with water. The organic layer was separated and the solvent removed under reduced pressure. The residue was chromatographed on silica gel eluting with dichloromethane: acetone (99: 1) to give 6-cyano-2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one (16.58 g). we get.

¹ H-NMR (CDCl ₃ ): delta 1.2 (d, 3H); 1.30 (s, 3H); 1.5 (s,

3H); 2.8 (q, 1H); 7.0 (d, 1H); 7.70 (d, 1H); 8.1 (s, 1H).

REFERENCE EXAMPLE 4 Preparation of Compounds of Formula 6

A) Preparation of a compound of formula 6 wherein Y is nitro, R * and R ^{2 are} methyl and R ^{8 is} hydrogen.

To a solution of 6-nitro-2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one (40.0 g, 0.170 mol) in methanol (400 ml) at room temperature was added 6.4 g (0.170 mol) of sodium boron. -hydride is added. After stirring for 2 hours, the solvent was removed under reduced pressure and the residue was stirred with water / dichloromethane. The organic phase was then separated and concentrated under reduced pressure to give 42.2 g of 6-nitro-2,2,3-trimethyl-4-hydroxy-3,4-dihydro-2H-1-benzopyran as an oil.

1 H-NMR (CDCl 3): delta 1.05 (d, 3H); 1.4 (s, 3H); 1.45 (s,

-523H); 2.0-2.2 (m, 2H); 4.4 and 4.9 (triplets, cis and trans, 1H); 6.85 (m, 1H); 8.05 (m, 1H); 8.4 (m, 1H).

B) Preparation of compounds of formula 6 wherein Y is bromo or cyano, R 1 · and R ^{2 are} methyl and r 5 and hydrogen

We do the same as above, but with 6-nitro-

Replacing 2,3,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one with the 6-cyano analogue of compound (5) or the 6-bromo analogue of compound (3b), and following the procedure of Example 4A above, the following compounds of formula (6) are obtained:

6-cyano-2,2,3-trimethyl-4-hydroxy-3,4-dihydro-2H-1-benzopyran;

6-Bromo-2,2,3-trimethyl-4-hydroxy-3,4-dihydro-2H-1-benzopyran, oil;

¹ H-NMR (CDCl 3): δ 1.0 (d, 3H); 1.3 (s, 6H); 2.0 (m, 1H);

4.8 (d, 1H); 6.7 (d, 1H); 7.25 (d, 1H); 7.5 (s, 1H).

REFERENCE EXAMPLE 5 Preparation of Compounds of Formula 7

A) Preparation of a compound of formula 7 wherein Y is nitro, R 1 and R ^{2 are} methyl, and R 1 is hydrogen.

31.1 g (0.131 mol) of 6-nitro-2,2,3-trimethyl-4-hydroxy

A solution of 3,4-dihydro-2H-1-benzopyran and 2.5 g (0.013 mol) of p-toluenesulfonic acid in 875 ml of toluene was refluxed for 18 hours and the water was removed with a Dean-Stark water separator. The cooled solution was washed with aqueous sodium bicarbonate solution and the organic phase was separated. The solvent was evaporated under reduced pressure to give 30 g of 6-nitro-2,2,3-trimethyl-53-

til-2H-1-benzopyran was obtained as an oil.

¹ H-NMR (CDCl ₃ ): δ 1.45 (s, 6H); 1.9 (s, 3H); 6.15 (s,

1H); 6.8 (d, 1H); 7.8 (s, 1H); 8.0 (d, 1H).

B) Preparation of Compounds of Formula 7 in which Y is bromo or cyano, R ¹ - and R ^{1 are} methyl and r 5 and r ^{6 are} hydrogen

Similarly to the foregoing, however, 6-nitro-2,2,3-trimethyl-4-hydroxy-3,4-dihydro-2H-1-benzopyran is replaced by a compound of formula (6) in which Y is a bromine atom or a cyano group and 5A. By following the procedure of Reference Example 7, the following compounds of formula (7) are prepared:

6-cyano-2,2,3-trimethyl-2H-1-benzopyran, oil;

6-bromo-2,2,3-trimethyl-2H-1-benzopyran, oil, ¹ H NMR (CDC1 _3): delta 1.4 (s, 6H); 1.8 (s, 3H); 6.0 (s, 1H);

6.6 (d, 1H); 7.0 (s, 1H); 7.1 (d, 1H).

Reference Example 6 Preparation of Compounds of Formula (b)

Preparation of the compound of formula (b) wherein R ^ and R ² is methyl and R ^ and R ^ H

3-Hydroxy-3-methyl-2-butanone (10.5 ml, 10.2 g, 0.1 mol) was cooled to -5 ° C and phosphorus tribromide (3.75 ml, 0.04 mol) was added dropwise. After 1 hour at room temperature, the mixture was cooled and diluted with water and diethyl ether. The organic layer was separated, washed with water, dried and evaporated to give crude 3-bromo-3-methyl-2-butanone (12.04 g, 73%) as an oil. ¹ H-NMR (CDCl 3):? 1.9 (s, 3H); 2.45 (s, 3H).

• ·· ·

Reference Example 7 Preparation of Compounds of Formula (d)

Preparation of a compound of formula (d) wherein a solution of 5-iodosalicylic acid Y (0.00378 mol) in 4 ml of anhydrous tetrahydrofuran at 0 ° C in 11.4 ml of a 1.0 M solution of borane-tetrahydrofuran solution was added dropwise. The mixture is kept at room temperature for 15 minutes and then refluxed for 2 hours. The solution was cooled, water and ethyl acetate were added, the organic layer was separated and evaporated to dryness. The crude product residue was washed with pentane to give 0.8 g (84.21%) of 2-hydroxy-5-iodobenzyl alcohol, m.p. 125 ° C.

Reference Example 8 Preparation of compounds of formula (e)

A) Preparation of ____ (e) A compound of formula I wherein Y is iodine, ^R1 and · methyl and hydrogen and

0.63 g (0.00252 mol) of 2-hydroxy-5-iodobenzyl alcohol, 0.42 g (0.00254 mol) of 3-bromo-3-methyl-2-butanone and 0.42 g of (00377 mol) of potassium carbonate in 7 ml of methyl ethyl ketone was refluxed for 3 hours. A further equivalent (0.42 g, 0.00254 mol) of 3-bromo-3-methyl-2-butanone was then added. After refluxing for an additional 3 hours, the mixture was cooled and washed successively with water, aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was evaporated to give crude 3- (2-hydroxymethyl-4-iodophenoxy) -3-methyl-2-butanone (0.88 g, 100%).

we get.

B) ____ Preparation of a compound of formula (e) wherein Y is bromo, R ⁴ and R ^{2 are} methyl, and R ⁸ and R ^{8 are} hydrogen.

The same procedure as above, but substituting 2-hydroxy-5-iodobenzyl alcohol with 2-hydroxy-5-bromobenzyl alcohol and following the procedure of Reference Example 8A above, gives the following compound (e): we produce:

3- [2- (hydroxymethyl) -4-bromophenoxy] -3-methyl-2-butanone, oil;

⁴ H-NMR (CDCl 3): delta 1.5 (s, 6H); 2.2 (s, 1H); 2.25 (s,

3H); 4.7 (d, 2H); 6.4 (d, 1H); 7.25 (m, 1H); 7.5 (d, 1H).

REFERENCE EXAMPLE 9 Preparation of Compounds of Formula (f)

A) ____ Preparation of a compound of formula f wherein Y is iodine, R ⁴ and R ^{2 are} methyl and R ⁸ and R ^{8 are} hydrogen

A mixture of 0.84 g (0.00252 mol) of 3- [2- (hydroxymethyl) -4-iodophenoxy] -3-methyl-2-butanone and 0.86 g (0.00252 mol) of triphenylphosphine hydrobromide in 5 ml was heated in acetonitrile at 90 ° C for 2.5 hours. After evaporation, the crude product is washed with ether and dissolved in 3 ml of ethanol. Hot isopropyl ether (8 mL) was added to the solution until a light precipitate formed and the solution was allowed to stand at room temperature overnight. The crystalline product was collected by filtration to give 0.77 g (50%) of 2- (1-methyl-2-oxopropyloxy) -5-iodobenzyltriphenylphosphonium bromide, m.p. 230 ° C.

• ·· · »4

-56Β) ____ Preparation of a compound of formula (f) in which Y is a bromine atom, R ^X and R ^{2 are} methyl and R ⁸ and R ^{8 are} hydrogen.

The same procedure is followed except that 3- [2- (hydroxymethyl) -4-iodophenoxy] -3-methyl-1-butanone is 3- [2- (hydroxymethyl) -4-bromophenoxy]. Is replaced with -3-methyl-2-butanone and following the procedure of Reference Example 9A, above, the following compound (f) is prepared:

2- (1-methyl-2-oxopropyloxy) -5-bromobenzyl triphenylphosphonium bromide, m.p. 240 ° C.

Reference Example 10

Alternative process for the preparation of compounds of formula (7)

A) Preparation of a compound of formula 7 wherein Y is iodine, R ^X and R ^{2 are} methyl and R ⁸ and R ^{8 are} hydrogen.

To a suspension of 0.71 g (0.00108 mol) of 2- (1-methyl-2-oxo-propyloxy) -5-iodobenzyl-triphenyl-phosphonium bromide in 3 ml of ethanol at room temperature was added 0.025 g of sodium in 1 ml of absolute ethanol. ice. After 12 hours at room temperature, diethyl ether and water were added. The organic layer was separated, dried and evaporated. The residue was chromatographed on silica gel using dichloromethane: heptane (50:50, v / v) as eluent to give 0.29 g (85%) of 6-iodo-2,2,3-trimethyl-1 (2H) -benzopyran as an oil.

1 H-NMR (CDCl ₃ ): delta 1.4 (s, 6H); 1.8 (s, 3H); 6.0 (s, 1H);

6.55 (d, 1H); 7.2 (d, 1H); 7.35 (d, 1H).

-58-ethyl-2H-1-benzopyran is obtained in the form of an oil. MS: 242 (M < ⁺ >).

We do the same as above, but the 6-bromo

2,2,3-Trimethyl-2H-1-benzopyran is replaced by 6-iodo-2,2,3-trimethyl-2H-1-benzopyran and following the procedure described above, 6- (trifluoromethyl) -2,2,3- trimethyl 2H-1-benzopyran was obtained in 94% yield.

B) Preparation of a compound of formula (9) wherein Z is pentafluoroethyl, R ¹ and R ^ is methyl and R ° is hydrogen and R

In the same manner as above, however, potassium trifluoroacetate is replaced by potassium pentafluoroacetate and following the procedure of Reference Example 11A above, the following compound of formula 9 is prepared:

6- (pentafluoroethyl) -2,2,3-trimethyl-2H-1-benzopyran, oil; MS: 292 (M < ⁺ >).

REFERENCE EXAMPLE 12 Preparation of Compounds of Formula 10

A) Preparation of a compound of formula 10 wherein N is nitric and R is methyl and H

To a solution of 10.0 g (0.0457 mol) of 6-nitro-2,2,3-trimethyl-2H-1-benzopyran in 200 ml of dichloromethane at 0 ° C was 13.5 g (0.0548 mol) of M-chloroperbenzoic acid of a purity of% is added. After stirring for 18 hours at room temperature, the mixture was washed successively with water, aqueous sodium bicarbonate solution, water and then aqueous sodium hydroxide solution. The organic layer was separated and concentrated under reduced pressure to give 9.96 g (93%) of -nitro-2,2,3-trimethyl-3,4-di ..... .. .... J ....

• * «. · 59hydro-3,4-epoxy-2H-1-benzopyran is obtained.

¹ H-NMR (CDCl ₃ ): δ 1.3 (s, 3H); 1.55 (s, 3H); 1.60 (s,

3H); 3.8 (s, 1H); 6.9 (d, 1H); 8.15 (d, 1H); 8.30 (s, 1H).

B) Preparation of a compound of Formula 10 wherein R1 is cyano or trifluoromethyl and R2 is methyl and R1 and R1 are hydrogen

We do the same as above, but with 6-nitro-

2,2,3-Trimethyl-2H-1-benzopyran is replaced by compounds of formula (7) or (9) and following the procedure of Reference Example 12A above, the following compounds of formula (10) are obtained:

6-cyano-2,2,3-trimethyl-3,4-dihydro-3,4-epoxy-2H-1-benzopyran, m.p. 122 ° C;

6- (trifluoromethyl) -2,2,3-trimethyl-3,4-dihydro-3,4-epoxy-2H-1-benzopyran, oil;

¹ H-NMR (CDCl ₃ ): δ 1.3 (s, 3H); 1.55 (s, 3H); 1.6 (s,

3H); 3.75 (s, 1H); 6.85 (d, 1H); 7.4-7.6 (m, 2H); and 6- (pentafluoroethyl) -2,2,3-trimethyl-3,4-dihydro-3,4-epoxy-2H-1-benzopyran, m.p. 50C.

REFERENCE EXAMPLE Preparation of Compounds of Formula 12

A) Preparation of a compound of formula (12) wherein R3 is nitro, R ² * 2-oxo-l, 2-dihydro-pyridin-l-yl, R, and R2 are hydrogen and methyl, and

9.93 g (0.0422 mol) of 6-nitro-2,2,3-trimethyl-3,4-dihydro-

A solution of 3,4-epoxy-2H-1-benzopyran, 8.04 g (0.0845 mol) of 2 (1H) -pyridinone and 2.5 ml of 40% ethanol in Triton B in 100 ml of dioxane was refluxed for 20 hours. boil.

The solution is cooled, water and ethyl acetate are added, the organic phase is separated off and the solvent is removed under reduced pressure. The residue was washed with diethyl ether and pentane to give 3.53 g of 6-nitro-2,2,3-trimethyl-

4- (2-oxo-1,2-dihydropyridin-1-yl) -3,4-dihydro-3-hydroxy-2H-benzopyran is obtained, m.p. 214 ° C.

X

THE

X

X

0 in which R is cyano, or trifluoromethyl; or pentafluoroethyl, Rf 2-oxo-l, 2-dihydro-l-yl-

R 1 and R ^{2 are} methyl and and hydrogen

We do the same as above, but with 6-nitro-

2,2,3-trimethyl-3,4-dihydro-3,4-epoxy-2H-1-benzopyran is replaced by compounds of the general formula (10), e.g.

Following the procedure of Reference Example 13A, the following compounds of Formula 12 were obtained:

6-cyano-2,2,3-trimethyl-4- (2-oxo-1,2-dihydropyridine-yl) -3,4-dihydro-3-hydroxy-2H-l-benzopyran; 1 H-NMR (CDCl 3): delta 1.10 (s, 3H); 1.5 (s, 3H); 4.6 (bs, 1H); 6.3 (m, 1H); 6.6 (s, 1H); 6.8 (d, 1H); 7.0 (d, 1H); 7.4-7.6 (m, 4H);

6- (trifluoromethyl) -2,2,3-trimethyl-4- (2-oxo-1,2-dihydropyridin-1-yl) -3,4-dihydro-3-hydroxy-2H-1 benzopyran, op. 178 ° C; and

6- (pentafluoroethyl) -2,2,3-trimethyl-4- (2-oxo-1,2-dihydropyridin-1-yl) -3,4-dihydro-3-hydroxy-2H-1-benzopyran, oil; MS: 403 (M < ⁺ >).

C) Preparation of Compounds of Formula 12 wherein R ² and R ² and R 4 and ésθ are hydrogen, r 3 and

We do the same, but in this case ·· .. · · λ • · · ·. · * · · ♦ 4 · «* · 99 ·» · 4 · ··

-61-6-nitro-2,2,3-trimethyl-3,4-dihydro-3,4-epoxy-2H-1-benzopyran (10), for example, as described in Reference Example 12, and replacing 2 (1H) pyridinone (2-oxo-1,2-dihydropyridine) with 2-oxo-pyrrolidine or 1-oxoisoindoline, and following the procedure of Reference Example 13A, to provide the following compounds of formula 12:

6-nitro-2,2,3-trimethyl-4- (2-oxo-pyrrolidin-l-yl) -3,4-dihydro-3-hydroxy-2H-l-benzopyran;

6-cyano-2,2,3-trimethyl-4- (2-oxo-pyrrolidin-l-yl) -3,4-dihydro-3-hydroxy-2H-l-benzopyran;

6- (trifluoromethyl) -2,2,3-trimethyl-4- (2-oxo-pyrrolidin-1-yl) -3,4-dihydro-3-hydroxy-2H-1-benzopyran;

6- (pentafluoroethyl) -2,2,3-trimethyl-4- (2-oxo-pyrrolidin

1-yl) -3,4-dihydro-3-hydroxy-2H-1-benzopyran;

6-nitro-2,2,3-trimethyl-4- (l-oxo-isoindolin-2-yl) -3,4-dihydro-3-hydroxy-2H-l-benzopyran;

6-cyano-2,2,3-trimethyl-4- (l-oxo-isoindolin-2-yl) -3,4-dihydro-3-hydroxy-2H-l-benzopyran;

6- (trifluoromethyl) -2,2,3-trimethyl-4- (1-oxo-isoindoline

2-yl) -3,4-dihydro-3-hydroxy-2H-1-benzopyran; and

6- (pentafluoroethyl) -2,2,3-trimethyl-4- (1-oxo-izoindolin2-yl) -3,4-dihydro-3-hydroxy-2H-l-benzopyran.

REFERENCE EXAMPLE 14 Preparation of Compounds of Formula 13

A) ____ Preparation of a compound of formula 13 wherein R 0 is nitro, R 2 -oxo-1,2-dihydropyridin-1-yl, R * and R ^{2 are} methyl, and R 1 and R 4 are hydrogen.

3.53 g (0.0107 mol) of 6-nitro-2,2,3-trimethyl-4- (2-oxo-62-

To a solution of 1,2-dihydropyridin-1-yl) -3,4-dihydro-3-hydroxy-2H-1-benzopyran in 150 ml of tetrahydrofuran was added 0.32 g of 80% sodium hydride. The mixture was refluxed for 16 hours. To the cooled solution was added water and ethyl acetate, and the organic layer was separated, dried and evaporated under reduced pressure to give 1.62 g of 6nitro-2,2,3-trimethyl-4- (2-oxo-1,2-dihydropyridine). l-yl) -2H-1-benzopyran, m.p. 200 ° C.

B) Preparation of Compounds of Formula (13) wherein a cyano group, a trifluoromethyl group or pentafluoroethyl group, R ⁴ 2-oxo-l, 2-dihydro-l-yl, R, and R ² is methyl and R ³ and Εθ is hydrogen

The same procedure was followed except that 6-nitro-2,2,3-trimethyl-4- (2-oxo-1,2-dihydropyridin-1-yl) -3,4-dihydro-3-hydroxy-2H-1-benzopyran was used. is replaced by other compounds of formula 12, such as those described in Reference Example 13, and following the procedure of Reference Example 14A, the following compounds of Formula 13 are obtained:

6-cyano-2,2,3-trimethyl-4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 213 ° C;

6- (trifluoromethyl) -2,2,3-trimethyl-4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 130 ° C; and

6- (pentafluoroethyl) -2,2,3-trimethyl-4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 125 ° C.

C) Preparation of Compounds of Formula 13 wherein R 1 and R ^{2 are} methyl, R 6 and R 4 are hydrogen, and R ³ and R ^{4 are of} variable importance

We do the same as above, but in this case-63-

6-nitro-2,2,3-trimethyl-3,4-dihydro-3,4-epoxy-2H-1-benzopyran with another compound of formula 12, such as that described in Reference Example 13; (1 H) -pyridinone, i.e. 2-oxo-1,2-dihydropyridine, is replaced by 2-oxo-pyrrolidine or 1-oxo-isoindoline, and following the procedure of Reference Example 14A, the following compounds of formula 13 are obtained:

6-nitro-2,2,3-trimethyl-4- (2-oxo-pyrrolidin-l-yl) -2H-l-benzopyran;

6-cyano-2,2,3-trimethyl-4- (2-oxo-pyrrolidin-l-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2,3-trimethyl-4- (2-oxo-pyrrolidinyl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2,3-trimethyl-4- (2-oxo-pyrrolidin

1- (i) -2H-1-benzopyran;

6-nitro-2,2,3-trimethyl-4- (l-oxo-isoindolin-2-yl) -4- (1-oxo-isoindolin-2-yl) -2H-1-benzopyran;

6-cyano-2,2,3-trimethyl-4- (1-oxo-isoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2,3-trimethyl-4- (1-oxo-isoindoline

2-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2,3-trimethyl-4- (1-oxo-izoindolin2-yl) -2H-l-benzopyran.

REFERENCE EXAMPLE 15 Preparation of Compounds of Formula 14

A) Preparation of a compound of formula (14) in which a nitro group, R ⁴ 2-oxo-l, 2-dihydro-l-yl, and R ⁴ are hydrogen and methyl, and

1.62 g (0.0052 mol) of 6-nitro-2,2,3-trimethyl-4- (2-oxo-64-

A solution of 1,2-dihydropyridin-1-yl) -2H-1-benzopyran in 10 ml of carbon tetrachloride containing 20 mg of benzoyl peroxide was heated to 60 ° C. N-bromosuccinimide (0.92 g, 0.0052 mol) was added and refluxed for 17 hours. To the cooled solution was added dichloromethane and an aqueous solution of ferrous sulfate, the organic phase was separated and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with dichloromethane: acetone (92.5: 7.5, v / v). The product was washed with a mixture of diethyl ether and pentane to give 1.49 g of 6-nitro-

2.2-Dimethyl-3- (bromomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran is obtained, m.p. 221 ° C.

B) ____ Preparation of compounds of formula 14 wherein R is cyano, trifluoromethyl-1-trifluoromethyl or pentafluoroethyl, (2-oxo-1,2-dihydropyridin-1-yl), R ¹ and R ¹ -methyl. and R and R 0 are hydrogen

We do the same as above, but with 6-nitro-

2,2,3-trimethyl-4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran is replaced by another compound of general formula (13), for example, as described in Reference Example 14, and following the procedure of Reference Example 15A to provide the following compounds of Formula 15:

6-cyano-2,2-dimethyl-3- (bromomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 180 ° C;

6- (trifluoromethyl) -2,2-dimethyl-3- (bromomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 130 ° C; and

6- (pentafluoroethyl) -2,2-dimethyl-3- (bromomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 112 ° C.

C) ____ Preparation of compounds of formula 14 wherein R * and R ^{2 are} methyl, R 4 and H and R ³ and R 4 are variable.

We do the same as above, but with 6-nitro-

2,2,3-trimethyl-3,4-dihydro-3,4-epoxy-2H-1-benzopyran, optionally with another compound of formula (13), prepared as in Reference Example 14, and 2 (1H) Pyridinone, i.e. 2-oxo-1,2-dihydropyridine, is replaced by 2-oxo-pyrrolidine or 1-oxo-isoindoline, and following the procedure of Reference Example 15A gives the following compounds of formula 14:

6-nitro-2,2-dimethyl-3- (bromomethyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (bromomethyl) -4- (2-oxo-pyrrolidin

1-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (bromomethyl) -4- (2-oxopyrrolidin-l-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (bromomethyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (bromomethyl) -4- (1-oxo-isoindoline

2-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (bromomethyl) -4- (1-oxo-izoindolin2-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (bromomethyl) -4- (1-oxo-isoindolin-2-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (bromomethyl) -4- (1-oxo-isoindolin-2-yl) -2H-1-benzopyran.

Reference Example 16

Alternative process Compounds of general formula (14)

-66előállítására

A) Preparation of a compound of formula (14) wherein the bromine atom is methyl, R 4 and hydrogen and R ^{4 are} 2-oxo-1,2-dihydropyridin-1-yl.

9.0 g (0.0248 mol) of 6-bromo-2,2-dimethyl-3- (hydroxymethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran 150 suspended in ml of toluene. To the suspension was added phosphorus tribromide (0.94 mL, 2.69 g, 0.0099 mol) and the mixture was refluxed for 2 hours. The solution was cooled, diluted with water and ethyl acetate, and the organic phase was separated and washed three times with brine, then dried and concentrated under reduced pressure. The residue was triturated with pentane and dried to give 9.94 g of 6-bromo-2,2-dimethyl-3- (bromomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-. benzopyran, m.p. 175 ° C.

Preparation B) ____Olyan (14) compounds in which a chlorine atom or a hydrogen atom, R - * - and a methyl group, R5 and R6 is hydrogen and R ⁴ of 2-oxo-pyrrolidin-l-yl

We do the same as above, but the 6-bromo

2,2-Dimethyl-3- (hydroxymethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran is replaced by another compound of Formula 26 and Reference Example 16A By following the procedure described in the following steps, the following compounds of formula (14) are obtained:

6-chloro-2,2-dimethyl-3- (bromomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 164 ° C; and

2,2-dimethyl-3- (bromomethyl) -4- (2-oxo-l, 2-dihydro-67-

1-yl) -2H-1-benzopyran, m.p. 160 ° C.

REFERENCE EXAMPLE 17 Preparation of Compounds of Formula 15

A) Preparation of a compound of Formula 15 wherein R ^{3 is} nitro, R ^{4 is} 2-oxo-1,2-dihydropyridin-1-yl, R 1 and R ^{2 are} methyl and and

6-Nitro-2,2-dimethyl-3- (bromomethyl) 4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran (0.1 g, 0.255 mmol) in 2 mL concentrated aqueous ammonium hydroxide and 2 mL of ethanol was stirred at room temperature for 4 hours. The solvent was evaporated and the residue was heated with 2 ml of ethanolic hydrogen chloride solution. Crystallization was initiated by addition of diethyl ether to give 0.07 g of 6-nitro-2,2-dimethyl-3- (aminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-. 1-Benzopyran is obtained in the form of its hydrochloride salt, m.p. 231 ° C.

B) Preparation of a compound of Formula 15 wherein R ^{3 is} cyano, trifluoromethyl or pentafluoroethyl, R ^{4 is} 2-oxo-1,2-dihydropyridin-1-yl, R ⁴ and R ^{2 are} methyl. and R 1 and R ^{3 are} hydrogen

We do the same as above, but with 6-nitro-

2,2-Dimethyl-3- (bromomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran is prepared by other methods such as those described in Reference Example 15 (14). ) and following the procedure of Reference Example 17A gives the following compound (14):

6-cyano-2,2-dimethyl-3- (aminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 175 ° C;

6- (trifluoromethyl) -2,2-dimethyl-3- (aminomethyl) - (2-oxo-68-)

1.2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 128 ° C; and

6- (pentafluoroethyl) -2,2-dimethyl-3- (aminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 128 ° C.

C) ____ Preparation of compounds of Formula 15 wherein R and R are hydrogen, and

R® and variable

We do the same as above, but with 6-nitro-

2.2-Dimethyl-3- (bromomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran is optionally prepared by other methods, such as those described in Reference Example 15 (14). ) and 2 (1H) -pyridinone, i.e. 2-oxo-1,2-dihydropyridine, is replaced by 2-oxopyrrolidine or 1-oxoisoindoline, and following the procedure of Reference Example 17A, compounds of formula:

6-nitro-2,2-dimethyl-3- (aminomethyl) -4- (2-oxo-pyrrolidin-l-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (aminomethyl) -4- (2-oxo-pyrrolidin-l-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (aminomethyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-l-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (aminomethyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (aminomethyl) -4- (1-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (aminomethyl) -4- (l-oxo-isoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (aminomethyl) -4- (l-oxo-isoindolin-2-yl) -2H-1-benzopyran; and

-696- (pentafluoroethyl) -2,2-dimethyl-3- (aminomethyl) -4-.

(L-oxoisoindolin-2-yl) -2H-l-benzopyran.

REFERENCE EXAMPLE 18 Preparation of Compounds of Formula 16

A) Preparation of ____Olyan (16) a compound wherein a nitro group, and R ¹ is methyl and R6 is hydrogen and

A solution of 33.0 g (0.151 mol) of 6-nitro-2,2,3-trimethyl-2H-1-benzopyran and 0.020 g of benzoyl peroxide in 330 ml of carbon tetrachloride was heated at 50 ° C and 26.8 g of N-bromosuccinimide (0.15 mol) was added. After refluxing for 18 hours, water and an aqueous solution of ferrous sulfate were added. The organic layer was separated and concentrated under reduced pressure. The residue was washed with pentane to give 40.45 g of 6-nitro-2,2-dimethyl-3- (bromomethyl) -2H-1-benzopyran, m.p. 107 ° C.

B) Preparation of a compound of Formula 16, p

^J wherein R a cyano group, a trifluoromethyl group or pentafluoroethyl group, and R ¹ is methyl and R ³ is hydrogen and R

We do the same as above, but with 6-nitro-

2,2,3-trimethyl-2H-1-benzopyran is replaced by a compound of formula (7) or (9), for example, as described in Reference Examples 5 and 11, and following the procedure of Reference Example 18A. Compounds of formula 16 are obtained:

6-cyano-2,2-dimethyl-3- (bromomethyl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (bromomethyl) -2H-1 benzopyran;

-706- (pentafluoroethyl) -2,2-dimethyl-3- (bromomethyl) -2H-1-benzopyran.

REFERENCE EXAMPLE 19 Preparation of Compounds of Formula 17

A) Preparation of a compound of formula 17 wherein R ^{3 is} nitro, R * and R ^{2 are} methyl, R ⁸ and R ^{8 are} hydrogen, and R ^{7 is} trifluoroacetamido.

To a suspension of 1.4 g (80%, 4.7 mmol) of sodium hydride in 2 mL of dimethylformamide is 0.53 g (4.7 mmol)

2.2.2-Trifluoroacetamide in 2 ml of dimethylformamide was added dropwise. After 1 hour at room temperature, 6-nitro-2,2-dimethyl-3-bromomethyl-2H-1-benzopyran (1.4 g, 4.7 mmol) was added and the mixture was heated to 70 ° C. Heat for 18 hours. The solution was cooled and diluted with water and ethyl acetate. The organic layer was separated and evaporated to give 0.51 g of 6-nitro-2,2-dimethyl-3- (trifluoroacetamido) methyl-2H-1-benzopyran.

¹ H-NMR (CDCl ₃ ): δ 1.5 (s, 6H); 4.15 (d, 2H); 6.25 (s, 1H); 6.85 (d, 1H); 6.9 (bs, 1H); 7.85 (s, 1H); 8.05 (d, 1H).

Preparation B) ____Olyan (17) compounds of the formula, β β 7 wherein R ¹ and R is methyl, R ^u and R is hydrogen, R ', p trifluoroacetamido group, and R ^J is variable

We do the same as above, but with 6-nitro-

2.2-Dimethyl-3- (bromomethyl) -2H-1-benzopyran is replaced by a suitable compound of formula (16), for example, as described in Reference Example 18, and following the procedure of Reference Example 19A. ):

6-cyano-2,2-dimethyl-3- (trifluoroacetamido) methyl-2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (trifluoroacetamidomethyl) -2H-1-benzopyran; and

6- (pentafluoroethyl) -2,2-dimethyl-3- (trifluoroacetamidomethyl) -2H-1-benzopyran.

REFERENCE EXAMPLE 20 Preparation of Compounds of Formula 18

A) Preparation of a compound of Formula 18 wherein R ^{2 is} nitro, R ² and R ^{2 are} methyl, and R ^{8 is} hydrogen and R * is trifluoroacetamido.

To a solution of 6-nitro-2,2-dimethyl-3- (trifluoroacetamidomethyl) -2H-1-benzopyran (0.5 g, 1.52 mmol) in dichloromethane (10 mL) at 0 ° C was added 0.45 g ( M-Chloroperbenzoic acid (70%, 1.52 mmol) was added. After stirring at room temperature for 16 hours, water and sodium bicarbonate were added and the organic layer was separated and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with a 95: 5 mixture of dichloromethane and acetone. 0.43 g of 6-nitro-2,2-dimethyl-3- (trifluoroacetamidomethyl) -3,4-dihydro-3,4-epoxy-2H-1-benzopyran is isolated.

¹ H-NMR (CDCl 3): delta 1.4 (s, 3H); 1.6 (s, 3H); 3.7 (dd, 1H); 3.85 (s, 1H); 4.15 (dd, 1H); 6.70 (bs, 1H); 6.95 (d, 1H); 8.2 (d, 1H); 8.30 (s, 1H).

B) ____Preparation of compounds of formula 18, »

wherein R 1 and R ^{2 are} methyl, R 4 and R ^{8 are} hydrogen, and R ^{2 is} hydrogen; trifluoroacetamido group and R ² represents a variable

The same procedure is followed, but 6-nitro-2,2-di-72-methyl-3- (trifluoroacetamidomethyl) -2H-1-benzopyran is prepared in a suitable manner, for example as described in Reference Example 19 (17). and following the procedure of Reference Example 20A, the following compounds of Formula 18 are prepared:

6-cyano-2,2-dimethyl-3- (trifluoroacetamido-ylmethyl) -3,4-dihydro-3,4-epoxy-2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (trifluoroacetamidomethyl) -3,4-dihydro-3,4-epoxy-2H-1-benzopyran; and

6- (pentafluoroethyl) -2,2-dimethyl-3- (trifluoroacetamidomethyl) -3,4-dihydro-3,4-epoxy-2H-1-benzopyran.

REFERENCE EXAMPLE 21 Preparation of Compounds of Formula 19

A) ____ Preparation of a compound of Formula 19 wherein R ^{2 is} nitro, R ² and R ^{2 are} methyl, and Ιΐθ is hydrogen, R ^{4 is} 2-oxo-1,2-dihydropyridin-1-yl, and R ^{7 is} trifluoro; acetamido group

0.4 g (1.16 mmol) of 6-nitro-2,2-dimethyl-3- (trifluoroacetamidomethyl) -3,4-dihydro-3,4-epoxy-2H-1-benzopyran, 0.22 g A mixture of 2 (1H) -pyridinone (2.32 mmol) and Triton B (0.05 mL) in dioxane (3 mL) was heated at reflux for 19 hours. The reaction mixture was diluted with water and ethyl acetate, and the organic layer was separated and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with a 95: 5 by volume mixture of dichloromethane and acetone. 0.1 g of 6-nitro-2,2-dimethyl-3- (trifluoroacetamidomethyl) -3,4-dihydro-3-hydroxy-4- (2-oxo-

1,2-dihydropyridin-1-yl) -2H-1-benzopyran is obtained, m.p. 158 ° C.

Β) ____ Preparation of compounds of formula 19 wherein R 1 and R ^{2 are} methyl and R ^{4 is} hydrogen.

2-oxo-1,2-dihydropyridin-1-yl; trifluoroacetamido and R 4 is variable

The same procedure is followed except that 6-nitro-2,2-dimethyl-3- (trifluoroacetamidomethyl) -3,4-dihydro-3,4-epoxy-2H-1-benzopyran is used in a suitable example, e.g. is replaced by a compound of formula (18) prepared as described above, and following the procedure of Example 21A, the following compound of formula (19) is prepared:

6-cyano-2,2-dimethyl-3- (trifluoro-acetamido-methyl) -3,4-dihydro-3-hydroxy-4- (2-oxo-l, 2-dihydro-l-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (trifluoroacetamidomethyl) -3,4-dihydro-3-hydroxy-4- (2-oxo-1,2-dihydropyridin-1-yl) -2H- l-benzopyran; and

6- (pentafluoroethyl) -2,2-dimethyl-3- (trifluoroacetamidomethyl) -3,4-dihydro-3-hydroxy-4- (2-oxo-1,2-dihydropyridin-1-yl) -2H- 1-benzopyran.

Example 1

Preparation of compounds of formulas I and IA wherein R 0 is lower alkyl or lower hydroxyalkyl and r 9 is hydrogen, lower alkyl or lower hydroxyalkyl

A) ____ Preparation of a compound of formula IA wherein R 1 is nitro, R 1 and R ^{2 are} methyl, R 6 and R 4 are hydrogen, R 2-oxo-1,2-dihydropyridin-1-yl, R 4

methyl and hydrogen

6-Nitro-2,2-dimethyl-3- (bromomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran (0.5 g, 1.27 mmol) and 40% aqueous methylamine (1.1 mL, 1.397 mmol) in methanol (12 mL) was stirred at room temperature for 4 hours. The solvents were evaporated under reduced pressure and water and ethyl acetate were added to the residue. After stirring, the organic phase is separated off and concentrated under reduced pressure. The residue was dissolved in diethyl ether and precipitated with pentane to give 0.31 g of 6-nitro-2,2-dimethyl-3- (methylaminomethyl) -4- (2-oxo)

1.2-dihydropyridin-1-yl) -2H-1-benzopyran is obtained, m.p. 128 ° C.

B) Preparation of a compound of formula I wherein R ^{3 is} nitro, and R ^{2 is} methyl, R ² and hydrogen, 2-oxo-1,2-dihydropyridin-1-yl, and R 1 is a variable compound.

In the same manner as above, however, the methylamine is replaced by dimethylamine and 2-hydroxyethylamine, and following the procedure of Example 1A, the following compounds of formula I are prepared:

6-nitro-2,2-dimethyl-3- (dimethylamino-methyl) -4- (2-oxo-

1.2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 222 ° C; and

6-nitro-2,2-dimethyl-3 - [(2-hydroxyethyl) aminomethyl] -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. . 225 ° C.

C) Preparation of a compound of formula I wherein R * and R ^{2 are} methyl, R 6 and hydrogen are R ² .

, r8 and R6 are variable

Proceed as above, but optionally using 6-nitro-2,2-dimethyl-3- (bromomethyl) -4- (2-oxo-1,2-dihydroxide). · '···' · ♦ ·· * ♦? · · * ·· · ♦ ·.:. · .. ·

-75-propyridin-1-yl) -2H-1-benzopyran is replaced by a suitable compound of formula (14), e.g. ° C-lower alkyl or lower-carbon hydroxyalkyl and R @ 3 is hydrogen, lower-carbon or lower-hydroxyalkyl, and following the procedure of Example 1A, the following compounds of formula I are prepared wherein R ° lower alkyl or lower hydroxyalkyl and hydrogen, lower alkyl or lower hydroxyalkyl:

6-nitro-2,2-dimethyl-3- (ethylamino) methyl-4- (2-oxo-2dihidropiridin-l-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (diethylamino) methyl-4- (2-oxo-

1,2-dihydropyridine-l-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- [N-methyl-N- (2-hydroxyethyl) aminomethyl] -4- (2-oxo-l, 2-dihydro-l-yl) -2 -lbenzopirán;

6-cyano-2,2-dimethyl-3- (methylamino) -4- (2-oxo-

1,2-dihydropyridine-l-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (dimethylamino-methyl) -4- (2-oxo-

1,2-dihydropyridine-l-yl) -2H-l-benzopyran;

6-Cyano-2,2-dimethyl-3 - [(2-hydroxyethyl) aminomethyl] -4- (2-oxo-l, 2-dihydro-l-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (ethylamino) methyl-4- (2-oxo-2dihidropiridin-l-yl) -2H-l-benzopyran;

6-Cyano-2,2-dimethyl-3- (diethylaminomethyl) -4- (2-oxo *)

1 »

1,2-dihydropyridine-l-yl) -2H-l-benzopyran;

6-Cyano-2,2-dimethyl-3- [N-methyl-N- (2-hydroxyethyl) amino-methyl] -4- (2-oxo-1,2-dihydropyridin-1-yl) - 2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (methylaminomethyl) 4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (dimethylamino) methyl-4- (2-oxo-1,2-dihydropyridine-l-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3 - [(2-hydroxyethyl) aminomethyl] -4- (2-oxo-1,2-dihydropyridine-l-yl) -2H-l benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (ethylamino-methyl) -4- (2-oxo-1,2-dihydropyridine-l-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (diethylaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- [N-methyl-N- (2-hydroxyethyl) aminomethyl] -4- (2-oxo-1,2-dihydropyridin-1-yl) - 2H-l-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (methylamino) methyl-4- (2-oxo-1,2-dihydropyridine-l-yl) -2H-l-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (dimethylamino-methyl) -4- (2-oxo-1,2-dihydropyridine-l-yl) -2H-l-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3 - [(2-hydroxyethyl) aminomethyl] -4- (2-oxo-1,2-dihydropyridine-l-yl) -2H-l benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (ethylamino) methyl-4- (2-oxo-1,2-dihydropyridine-l-yl) -2H-l-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (diethylamino) methyl-4- (2-oxo-1,2-dihydropyridine-l-yl) -2H-l-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- [N-methyl-N- (2-hydrogen ···· · · · · · · · · · · · · · · · · · · · · · · · · · ·

-77oxi-ethyl) -amino] -4- (2-oxo-l, 2-dihydro-l-yl) 2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (methylamino-methyl) -4- (2- oxopyrrolidin-l-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (dimethylaminomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (2-hydroxyethylaminomethyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (ethylamino) methyl-4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (diethylamino) methyl-4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- [N-methyl-N- (2-hydroxyethyl) aminomethyl] -4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran ;

6-cyano-2,2-dimethyl-3- (methylamino) methyl-4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (dimethylamino-methyl) -4- (2-oxo-pyrrolidin-l-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3 - [(2-hydroxyethyl) aminomethyl] -4- (2-oxo-pyrrolidin-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (ethylamino) methyl-4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (diethylaminomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6-Cyano-2,2-dimethyl-3- [N-methyl-N- (2-hydroxyethyl) amino-methyl] -4- (2-oxo-pyrrolidin-1-yl) -2H-1- benzopyran;

6 (trifluoromethyl) -2,2-dimethyl-3- (methylamino) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (dimethylaminomethyl) ···· ·

-784- (2-oxopyrrolidin-l-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3 - [(2-hydroxyethyl) aminomethyl] -4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (ethylaminomethyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (diethylamino) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- [N-methyl-N - [(2-hydroxyethyl) aminomethyl] -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (methylamino) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (dimethylamino) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3 - [(2-hydroxyethyl) aminomethyl] -4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (ethylamino) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (diethylamino) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- [N-methyl-N- (2-hydroxyethyl) aminomethyl] -4- (2-oxo-pyrrolidin-l-yl) - 2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (methylamino) methyl-4- (1-oxoisoindoline-2-yl) -2H-l-benzopyran;

Of 6-nitro-2,2-dimethyl-3- (dimethylamino-methyl) -4- (1-oxoisoindoline-2-yl) -2H-1-benzopyran;

Of 6-nitro-2,2-dimethyl-3 - [(2-hydroxyethyl) amino] -4- (l-oxo-isoindolin-2-yl) -2H-l-benzopyran;

-796-nitro-2,2-dimethyl-3- (ethylaminomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (diethylamino) methyl-4- (1-oxoisoindoline-2-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- [N-methyl-N- (2-hydroxyethyl) amino] -4- (1-oxo-isoindolin-2-yl) -2H-1-benzopyran ;

6-cyano-2,2-dimethyl-3- (methylamino) methyl-4- (1-oxoisoindoline-2-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (dimethylaminomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3 - [(2-hydroxyethyl) amino-methyl) -4- (l-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (ethylaminomethyl) -4- (1-oxoisoindol-2-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (diethylamino) methyl-4- (1-oxoisoindoline-2-yl) -2H-1-benzopyran;

6-Cyano-2,2-dimethyl-3- [N-methyl-N- (2-hydroxyethyl) aminomethyl] -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran ;

6- (trifluoromethyl) -2,2-dimethyl-3- (methylaminomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (dimethylaminomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3 - [(2-hydroxyethyl) aminomethyl] -4- (l-oxo-isoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (ethylaminomethyl) 4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (diethylamino) methyl-4- (l-oxo-isoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methyl-N- (2-hydroxy-80-)

ethyl) amino] -4- (1-oxo-isoindolin-2-i1) -2H-l-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (methylamino) methyl-4- (1-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (dimethylaminomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3 - [(2-hydroxyethyl) aminomethyl] -4- (l-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (ethylamino) methyl-4- (1-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (diethylaminomethyl) 4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran; and

6- (pentafluoroethyl) -2,2-dimethyl-3- [N-methyl-N- (2-hydroxyethyl) amino) methyl-4- (1-oxo-isoindolin-2-yl) - 2H-1benzopyran.

Example 2

Preparation of (I) and formula (IA), wherein Q _χ carbon atoms and R9 is hydrogen or lower alkyl, R is hydroxy or lower

A) Preparation of a compound of formula (I) wherein R 1 is nitro, R 1 and R 4 are methyl, R 1 and R 4 are hydrogen, 2-oxo-1,2-dihydropyridin-1-yl, hydroxy and R ^ methyl

6-Nitro-2,2-dimethyl-3- (bromomethyl) 4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran (0.30 g, 7.7 mmol) A mixture of 0.64 g (7.7 mmol) of N-methylhydroxylamine hydrochloride and 0.97 g (7.7 mmol) of potassium carbonate in 10 ml of ethanol is refluxed for 30 minutes. Water was added to the mixture and

Extract with -81 dichloromethane. The organic layer was separated and the solvent removed under reduced pressure. The residue was washed with diethyl ether to give 0.19 g of 6-nitro-2,2-dimethyl-3- (N-methyl-N-hydroxyaminomethyl) -4- (2-oxo-1,2-dihydropyridine).

1-yl) -2H-1-benzopyran, m.p. 159 ° C, is obtained.

B) Preparation of compounds of formula I wherein R ^{2 is} methyl, R ³ and R ^{8 are} hydrogen, R ⁴

2-oxo-1,2-dihydropyridin-1-yl and R ⁸ , R ⁸ and R ⁸ are variable

The same procedure as above, except that 6-nitro-2,2-dimethyl-3- (bromomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H- l-benzopyran compound, and optionally (14) prepared as described e.g. from a corresponding reference example 15. N-methyl-hydroxylamine hydrochloride was replaced with HNR ⁸ R ⁸ amine, the latter R ⁸ is hydroxy or lower alkoxy and R ^J hydrogen or lower alkyl, and following the procedure of Example 2A, the following compounds of formula I are prepared:

6-nitro-2,2-dimethyl-3- (hydroxyamino) methyl-4- (2-oxo-

1.2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. > 25 ° C;

6-nitro-2,2-dimethyl-3- (methoxyamino) methyl-4- (2-oxo-

1.2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 196 ° C;

6-cyano-2,2-dimethyl-3- (N-methyl-N-hydroxyaminomethyl) 4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, op. 165 ° C;

6- (trifluoromethyl) -2,2-dimethyl-3- (hydroxyaminomethyl) 4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 90 ° C;

-826- (trifluoromethyl) -2,2-dimethyl-3- (methoxyaminomethyl) 4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, 160 ° C;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methylhydroxyaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 145 ° C;

6- (pentafluoroethyl) -2,2-dimethyl-3- (hydroxyamino) methyl-4- (2-oxo-l, 2-dihydro-l-yl) -2H-l-benzopyran; oil, 1 HNMR (CDCl ₃ ): delta 1.6 (s, 2H); 3.6 (s, 2H); 5.35 (bs, 2H); 6.3-7.6 (m, 7H);

6-bromo-2,2-dimethyl-3- (hydroxyamino) methyl-4- (2-oxo-

1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 170 ° C;

6-chloro-2,2-dimethyl-3- (hydroxyamino) methyl-4- (2-oxo-

1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 113 ° C;

2,2-dimethyl-3- (hydroxyaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 106 ° C.

C) Preparation of Compounds of Formula I wherein R ^{2 is} methyl, R 6 and R ^{2 are} hydrogen and R ² , r 4, R 4 and R 4 are each variable.

The same procedure as above, except that 6-nitro-2,2-dimethyl-3- (bromomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1- benzopyran is replaced by a suitable compound of formula (14), e.g. alkoxy and R @ 3 is hydrogen or lower alkyl, and following the procedure of Example 2A, the following compounds of formula I are prepared:

-836-nitro-2,2-dimethyl-3- (ethoxy-methyl) -4- (2-oxo-

1,2-dihydropyridine-l-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (N-methyl-N-methoxy-amino) methyl-4- (2-oxo-l, 2-dihydro-l-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (N-ethyl-N-hydroxyamino) methyl-4- (2-oxo-l, 2-dihydro-l-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (hydroxyamino) methyl-4- (2-oxo-

1,2-dihydropyridine-l-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (methoxyamino) methyl-4- (2-oxo-

1,2-dihydropyridine-l-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (ethoxy-methyl) -4- (2-oxo-

1,2-dihydropyridine-l-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (N-methyl-N-methoxyaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N-ethyl-N-hydroxyaminomethyl) 4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (ethoxy-methyl) -4- (2-oxo-l, 2-dihydro-l-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methyl-N-methoxaminaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran ;

6- (Trifluoromethyl) -2,2-dimethyl-3- (N-ethyl-N-hydroxyaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2- (1-benzopyran) ;

6- (Pentafluoroethyl) -2,2-dimethyl-3- (N-methyl-N-hydroxyaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzop i on it;

6- (pentafluoroethyl) -2,2-dimethyl-3- (methoxyamino) methyl-4- (2-oxo-l, 2-dihydro-l-yl) -2H-1-benzopyran;

846- (pentafluoroethyl) -2,2-dimethyl-3- (ethoxycarbonylmethyl-amino) methyl-4- (2-oxo-l, 2-dihydro-l-yl) -2H-l-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-methyl-N-methoxyamino) methyl-4- (2-oxo-l, 2-dihydro-l-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-ethyl-N-hydroxyamino) methyl-4- (2-oxo-l, 2-dihydro-l-yl) - (2-oxo -l, 2dihidropiridin-l-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (N-methyl-N-hydroxyamino) methyl-4 - ((2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (hydroxyaminomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (methoxyaminomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (ethoxy-methyl) -4- (2-oxopyrrolidin-l-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (N-methyl-N-methoxy-amino) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (N-ethyl-N-hydroxy-amino) -4 (2-oxopyrrolidin-l-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N-methyl-N-hydroxyamino) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (hydroxyamino) methyl-4- (2-oxopyrrolidin-l-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (methoxyaminomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (ethoxyaminomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N-methyl-N-methoxy-amino-methyl) -4-85 (2-oxopyrrolidin-l-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (N-ethyl-N-hydroxy-amino) -4 (2-oxopyrrolidin-l-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methyl-N-hydroxyamino) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (hydroxyaminomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -dimethyl-3- (methoxy-methyl) 4- (2-oxo-pyrrolidin-l-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (ethoxycarbonylmethyl-amino) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methyl-N-methoxyamino) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-ethyl-N-hydroxyamino) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimeti1-3- (N-methyl-N-hydroxyamino) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (hydroxyamino) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (methoxyaminomethyl) 4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (ethoxycarbonylmethyl-amino) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-methyl-N-methoxaminomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-ethyl-N-hydroxyaminomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (N-methyl-N-hydroxyaminomethyl) 4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

-866-nitro-2,2-dimethyl-3- (hydroxyamino) methyl-4- (1-oxoisoindoline-2-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (methoxyamino) methyl-4- (1-oxoisoindoline-2-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (ethoxy-methyl) -4- (l-oxoisoindoline-2-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (N-methyl-N-methoxy-amino) methyl-4- (1-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (N-ethyl-N-hydroxyamino) methyl-4- (1-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (N-methyl-N-hydroxyamino) methyl-4- (l-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (hydroxyaminomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (methoxyamino) methyl-4- (1-oxoisoindoline-2-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (ethoxy-methyl) -4- (l-oxoisoindoline-2-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (N-methyl-N-methoxyaminomethyl) 4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N-ethyl-N-hydroxyamino) methyl-4- (l-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methyl-N-hydroxyaminomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (hydroxyaminomethyl) 4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (methoxyaminomethyl) 4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (ethoxyaminomethyl) · ·

-874- (l-oxoisoindolin-2-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methyl-N-methoxyamino) methyl-4- (1-oxo-isoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-ethyl-N-hydroxyamino) methyl-4- (l-oxo-isoindolin-2-yl) -2H-l-benzopyran; 6- (pentafluoroethyl) -2,2-dimethyl-3- (N-hydroxyamino meti1-N-methyl) -4- (l-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (hydroxyaminomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (methoxyaminomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (ethoxyaminomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-methyl-N-methoxyamino) methyl-4- (1-oxo-isoindolin-2-yl) -2H-l-benzopyran; and

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-ethyl-N-hydroxyaminomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran.

EXAMPLE 3

Preparation of Compounds of Formula I wherein R ^{8 is} -COR ² and R ^{2 is} H

A) ____ Preparation of a compound of formula I wherein R ^{8 is} nitro, R * and R ^{2 are} methyl, R ⁸ and R ^{8 are} hydrogen, 2-oxo-1,2-dihydropyridin-1-yl, R ^{8 is} hydrogen and R ^{J is} -CO ^14, wherein R ^{42 is} hydrogen

6-Nitro-2,2-dimethyl-3- (aminomethyl) 4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran (0.5 g, 1.53 mmol) 10 ml of methyl formate solution for 27 hours at reflux • · · ·

Meanwhile, bring to a boil. The solvent was evaporated under reduced pressure and the residue was washed with diethyl ether to give 0.42 g.

6-nitro-2,2-dimethyl-3- (formamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran is obtained, m.p. .

B) ___ Preparation of compounds of formula I wherein R ^{2 is} methyl, R ⁸ and R ^{8 are} hydrogen, R ^{4 is} 2-oxo-1,2-dihydropyridin-1-yl, R ^{8 is} hydrogen, R ⁸ 19 12

A group of the formula -COR wherein R ^{x is} hydrogen and R ² is variable

We do the same as above, but with 6-nitro-

2,2-Dimethyl-3- (aminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran is prepared in a suitable manner, for example as described in Reference Example 17 (15). and following the procedure of Example 3A, the following compounds of formula (I) are prepared:

6-cyano-2,2-dimethyl-3- (formamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 165 ° C; and

6- (trifluoromethyl) -2,2-dimethyl-3- (formamidomethyl) -4 (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 169 ° C. C) ___ Preparation of compounds of formula I wherein R * and R ^{2 are} methyl, R ⁸ and R ^{8 are} hydrogen, R ^{8 is} -COR ² , wherein R ^{2 is} H, and R ² , R ⁴ and R ⁸ means variable

The same procedure as above, except that 6-nitro-2,2-dimethyl-3- (aminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H- 1-benzopyran is a suitable one such as that described in Reference Example 17 or Example 1 or Example 2.

Is replaced by the compound of formula (15) prepared in -89 and following the procedure of 3A gives the following compound (I):

6-nitro-2,2-dimethyl-3- (N-methylformamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (N-formamido) -4 (2-oxo-l, 2-dihydro-l-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (N-methoxy-formamido-ylmethyl) -4- (2-oxo-l, 2-dihydro-l-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N-formamido) -4 (2-oxo-l, 2-dihydro-l-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (N-hydroxy-phosphoramoylmethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N-methoxy-formamido-ylmethyl) -4- (2-oxo-l, 2-dihydro-l-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methylformamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-hydroxyformamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methoxy-formamidometil) -4- (2-oxo-l, 2-dihydro-l-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (formamidomethyl) 4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-methylformamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-hydroxy-formamidometil) -4- (2-oxo-l, 2-dihydro-l-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-methoxy-formamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

-906-nitro-2,2-dimethyl-3- (N-methylformamidomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (N-formamido) -4 (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (N-methoxy-formamidomethyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N-methylformamidomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N-formamido) -4 (2-oxopyrrolidin-l-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N-methoxy-formamido-ylmethyl) -4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methylformamidomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-hydroxy-formamidomethyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methoxy-formamidomethyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (l-aza-ylmethyl) 4- (2-oxo-pyrrolidin-l-yl) -2H-l-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-methylformamidomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-hydroxyformamidomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-methoxy-formamidomethyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (N-formamido) -4 (1-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (N-formamido meti1) -4-91 (1 οχο isoindolin-2-yl) -2Η-1-benzopyran;

6-nitro-2,2-dimethyl-3- (N-methoxy-formamido) -4 (1-oxo-isoindolin-2-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N-formamido) -4 (l-oxoisoindolin-2-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N-formamido) -4 (1-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (N-methoxy-formamido) -4 (l-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methylformamidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-hydroxy-formamidometil) -4- (l-oxo-isoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methoxyformamidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

- (pentafluoroethyl) -2,2-dimethyl-3- (formamethylmethyl) 4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-methylformamidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-hydroxyformamidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran; and

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-methoxy-formamidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran.

Example 4

Preparation of compounds of formula (I)

ben r8 hydrogen, low carbon or alkyl few C alkomos alkalkoxy; and R ^. -COR ^ ² general A group of formula 12 wherein R ^{ώ is} low carbon or alkyl

a low-carbon fluoroalkyl group

.... «..« ...

-92Α) ____ Preparation of a compound of formula (I) wherein R ^{2 is} nitro, R ² and R ^{2 are} methyl, and R ^{2 is} hydrogen, R ^{4 is} 2-oxo-1,2-dihydropyridin-1-yl, R ² hydrogen; and R ^{2 is} -COR ² ; wherein R ^{2 is} trifluoromethyl

6-Nitro-2,2-dimethyl-3- (aminomethyl) 4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran (0.5 g, 1.53 mmol) and a solution of triethylamine (0.25 mL, 1.8 mL) in dichloromethane (20 mL) at 0 ° C were added 0.26 mL (1.8 mmol) of trifluoroacetic anhydride and the mixture was stirred at room temperature for 4 hours. After addition of water, the organic phase is separated and evaporated. The residue was triturated with diethyl ether to give 0.53 g of 6-nitro-2,2-dimethyl-3- (trifluoroacetamidomethyl) -4- (2-oxo)

1,2-dihydropyridin-1-yl) -2H-1-benzopyran is obtained, m.p. 189 ° C.

B) ___ Preparation of compounds of formula I wherein R ^{2 is} methyl, R ² and hydrogen, R ^{4 is} 2-oxo-1,2-dihydropyridin-1-yl and R ^{2 is} -COR ² ; wherein R ^{x is} trifluoroacetyl and R ² , r 8 and R ¹² are variable

The same procedure as above, except that 6-nitro-2,2-dimethyl-3- (aminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran is optionally used is replaced by a suitable compound of formula (15) or (IA), for example, as described in Reference Example 17 or Example 1 or 2, and following the procedure of Example 4A, the following compounds of formula (I) are prepared:

6-nitro-2,2-dimethyl-3- (N-methyl trifluoroacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, *

-93 • · ··

V op. 178 ° C;

6-cyano-2,2-dimethyl-3- (trifluoroacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 190; and

6- (trifluoromethyl) -2,2-dimethyl-3- (trifluoroacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 168 ° C.

C) Preparation of Compounds of Formula (I) wherein R 1 and Methyl, R 6 and H, -CO 2 and -12 are variable

The procedure is the same as described above, except that 6-nitro-2,2-dimethyl-3- (aminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1- benzopyran with a suitable compound of formula (15) or (IA), such as that prepared in Reference Example 17 or Example 1 or 2, and trifluoroacetic anhydride with another anhydride of formula (R or a lower C 1 -C 7 fluoroalkyl group, or a suitable acid halide of formula R 1 COd or R 1 COCO, wherein R ¹ -C 4 lower alkyl is obtained, and following the procedure of Example 4A, the following compounds of formula I we produce:

6-nitro-2,2-dimethyl-3- (acetamido) methyl-4- (2-oxo-2dihidropiridin-l-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (propionamido-methyl) -4- (2-oxo-

1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (isobutanamidomethyl) -4- (2-oxo)

1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (acetamidomethyl) -4- (2-oxo-1,2,2 * * ·· · ··· * ····

dihydropyridin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (pentafluoro-propionamido-methyl) 4- (2-oxo-l, 2-dihydro-l-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N-methyl trifluoroacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (pentafluoro-propionamido-methyl) 4- (2-oxo-l, 2-dihydro-l-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (acetamidomethyl) -4- (2-oxo-l, 2-dihydro-l-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-trifluoroacetamido) methyl-4- (2-oxo-1,2-dihydropyridine-l-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (pentafluoropropionamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (acetamidomethyl) -4- (2-oxo-l, 2-dihydro-l-yl) -2H-l-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-methyltrifluoroacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (pentafluoropropionamido) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (acetamido) methyl-4- (2-oxopyrrolidin-l-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (trifluoroacetamidomethyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (N-methyl-trifluoroacetamidomethyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

.......... _á ....

• * * _- • ·· · '«· · * · ·· ··» · .. ·

-956-nitro-2,2-dimethyl-3- (pentafluoro-propionamido-methyl) 4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (acetamidomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (trifluoroacetamido) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (N-methyltrifluoroacetamidomethyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (pentafluoro-propionamido-methyl) 4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (acetamidomethyl) -4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (trifluoro-acetamidomethyl) -4- (2-oxo-pyrrolidin-l-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methyltrifluoroacetamidomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (pentafluoropropionamidomethyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (acetamidomethyl) -4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (trifluoroacetarimidomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-N-methyl-trifluoroacetamido) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (pentafluoropropionamidomethyl) -4- (2-oxopyrrolidin-1-yl) -2,5-benzopyran;

6-Nitro-2,2-dimethyl-3- (acetamidomethyl) -4- (1-oxo ···· · · ...

• · ♦ ·· · * · *.

-96izoindolin-2-yl) -Η-1-benzopyran;

6-nitro-2,2-dimethyl-3- (trifluoroacetamido) -4 (l-oxoisoindolin-2-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (N-methyl-trifluoro-acetamidomethyl) -4- (l-oxo-isoindolin-2-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (pentafluoro-propionamido) methyl-4- (l-oxo-isoindolin-2-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (acetamido) methyl-4- (1-oxoisoindoline-2-yl) -N-l-benzopyran;

6-cyano-2,2-dimethyl-3- (trifluoroacetamido) methyl-4- (1-oxo-isoindolin-2-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N-methyltrifluoroacetamidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (pentafluoro-propionamido-methyl) 4- (1-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (acetamidomethyl) -4- (l-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (trifluoroacetamidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methyl-trifluoroacetamido-meti1) -4- (1-oxo-isoindolin-2-yl) -2H-1-benzopyran;

- (trifluoromethyl) -2,2-dimethyl-3- (pentafluoropropionamidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (acetamidomethyl) -4- (l-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (trifluoroacetamidomethyl) -4- (1-oxo-indolin-2-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-methyl trifluoromethanesulfonate 97acetamido) methyl-4- (l-oxo-isoindolin-2-yl) -2H-1-benzopyran; and

6- (pentafluoroethyl) -2,2-dimethyl-3- (pentafluoropropionamidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran.

Example 5

So ( I) preparation of compounds of the general formula By persons R ⁸ Q 19 is hydroxy and R is -COR ¹ - group, wherein R ^ ^{2 is} lower or lower alkyl fluoroalkyl A) Yes Preparation of a compound of formula (I) in which R ³ trifluoromethyl; and R ^{2 is} methyl. R ⁵ and R ⁶ hydrogen, 2-oxo-1,2-dihydropyridin-1-yl- group, R ⁸ hydroxy; and R ^{8 is} -COR 4 · ² group, 1 9 in which R ^{1 is} trifluoromethyl 0.33 g (0.9 mmol) 6- (trifluoromethyl) -2,2-dimethyl-2-

A solution of (hydroxyaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-benzopyran in 9 ml of dichloromethane was cooled to 0 ° C and 0.12 ml of 0 The reaction mixture was treated with triethylamine (9 mmol) and trifluoroacetic anhydride (0.12 mL, 0.9 mmol) and stirred at 0 ° C for 2.5 h. Water was added, the organic layer was separated, washed with water and evaporated after drying. The crude product obtained is chromatographed on silica gel using dichloromethane: methanol (95: 5, v / v) as the eluent. The oil was isolated by crystallization from ether, 0.21 g of 6- (trifluoromethyl) -2,2-dimethyl-3- (N-hydroxy trifluoroacetamidomethyl).

4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran is obtained, m.p. 208 ° C.

-98Β) ____ Preparation of a compound of formula I wherein R ^{3 is} nitro, R ⁴ and R ^{2 are} methyl, R ⁸ and R ^{8 are} hydrogen, R ^{4 is} 2-oxo-1,2-dihydropyridin-1-yl, R ^{8 is} hydroxy. and R ^{9 is} -COR ⁴² in which

9

R is methyl

The same procedure was followed except that 6- (trifluoromethyl) -2,2-dimethyl-3- (hydroxyaminomethyl) -4- (2-oxo)

1,2-Dihydropyridin-1-yl) -2H-1-benzopyran is replaced by its 6-nitro analogue, trifluoroacetic anhydride, by acetic anhydride, and following the procedure of Example 5A, the following compound of formula I is prepared:

6-nitro-2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 245 ° C.

C) ___ Preparation of compounds of formula I wherein R ⁴ and R ^{2 are} methyl, R ⁸ and R ^{8 are} hydrogen, R ⁹ -COR ⁴² and R ³ , R ⁴ , R ⁸ and R ⁴² are variable

The same procedure is followed, but optionally 6- (trifluoromethyl) -2,2-dimethyl-3- (aminomethyl) -4-2H1-benzopyran may be used, for example, Reference Example 17 or Example 1. or a compound of formula (15) or (IA) prepared as described in Example 2 or optionally trifluoroacetic anhydride, wherein R ^{42 is} lower alkyl or lower fluoroalkyl. , and following the procedure of Example 5A, the following compounds were prepared:

6-nitro-2,2-dimethyl-3- (pentafluoropropionamidomethyl) 4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

-996-cyano-2,2-dimethyl-3- (N-methyltrifluoroacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (pentafluoro-propionamido-methyl) 4- (2-oxo-l, 2-dihydro-l-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (acetamidomethyl) -4- (2-oxo-l, 2-dihydro-l-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-trifluoroacetamido) methyl-4- (2-oxo-l, 2-dihydro-l-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (pentafluoro-propionamido-methyl) -4- (2-oxo-l, 2-dihydro-l-yl) -2H-l-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (acetamido) methyl-4- (2-oxo-l, 2-dihydro-l-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-methyltrifluoroacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (pentafluoropropionamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (acetamido) methyl-4- (2-oxopyrrolidin-l-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (trifluoroacetamido) methyl-4- (2-oxo-pyrrolidin-1-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (N-methyltrifluoroacetamidomethyl) -4- (2-oxopyrrolidinidin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (pentafluoropropionamidomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (acetamido) methyl-4- (2-oxo

-100pirrolidin l-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (trifluoro-acetamidomethyl) -4- (2-oxo-pyrrolidin-l-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (N-methyltrifluoroacetanimidomethyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (pentafluoro-propionamido-methyl) 4- (2-oxo-pyrrolidin-l-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (acetamidomethyl) -4- (2-oxo-pyrrolidin-l-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (trifluoroacetamidomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methyl trifluoroacetamidomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (pentafluoro-propionamido-methyl) -4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (acetamidomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (trifluoroacetamidomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-trifluoroacetamido) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (pentafluoro-propionamido-methyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (acetamidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (trifluoroacetamido) -4 (l-oxoisoindolin-2-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (N-methyltrifluoroacetamidinoethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

-1016-nitro-2,2-dimethyl-3- (pentafluoro-propionamido) methyl-4- (1-oxo-isoindolin-2-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (acetamidomethyl) -4- (1-oxoisoindolin-2-yl) -H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (trifluoroacetamido) -4 (l-oxoisoindolin-2-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N-methyltrifluoroacetamidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (pentafluoro-propionamido) methyl-4- (1-oxo-isoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (acetamido meti1) -4- (l-oxo-isoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (trifluoromethyl acetamidosmetil) -4- (1-oxo-isoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methyltrifluoroacetamidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (pentafluoro-propionamido-methyl) -4- (l-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (acetamido) methyl-4- (1-oxo-isoindolin-2-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (trifluoroacetamidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-methyltrifluoro-β-ethamidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (pentafluoro-propionamido-methyl) -4- (l-oxo-isoindolin-2-yl) -2H-l-benzopyran.

EXAMPLE 6

An alternative process for the preparation of compounds of formula I wherein R is hydrogen is low in carbon

-102alkilcsoport or lower alkoxy and R ^ COR ¹ group of formula, R is lower alkyl

A) ____ A method of producing front (I) Formula I, wherein R ⁴ and R ² is methyl, R @ ² trifluoromethyl, R ² and R ² is hydrogen, R ⁴ 2-oxo-2dihidropiridin-l-yl; R ^{2 is} hydrogen and R ^{2 is} -COR ⁴² wherein R is methyl

0.68 g (1.82 mmol) of 6- (trifluoromethyl) -2,2-dimethyl-3- (aminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H To a solution of -1-benzopyran and 0.3 mL (2.18 mmol) of triethylamine in 18 mL of dichloromethane was added 0.15 mL (2.18 mmol) of acetyl chloride at room temperature. The solution was stirred for 6 hours and then diluted with water. The organic layer was separated, dried and evaporated to give a crude product which was chromatographed on silica gel. The solvent was crystallized from ether to give 0.3 g of 6-trifluoromethyl-2, 2-dimethyl-3- (acetamidomethyl) as eluent. 4- (2-oxo-

1,2-dihydropyridin-1-yl) -2H-1-benzopyran is obtained, m.p. 174 ° C.

B) A process for the preparation of compounds of formula I wherein R ⁴ and R ^{2 are} methyl, R ² and R ^{2 are} hydrogen, R ^{4 is} 2-oxo-1,2-dihydropyridin-1-yl, R ^{2 is} hydrogen and R ^{J is} --COR ¹ - ¹ wherein R ^{42 is} methyl and R ² is variable

The same procedure was followed except that 6- (trifluoromethyl) -2,2-dimethyl-3- (aminomethyl) -4- (2-oxo-1,2-dihydropyridine-1) -yl) -2H-1-benzopyran is replaced by a corresponding compound of general formula (15) and following the procedure of Example 6A, the following compounds of formula (I) are prepared:

6-nitro-2,2-dimethyl-3- (acetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 218 ° C;

6-nitro-2,2-dimethyl-3- (methyl-propanamide) -4- (2-oxo-

1.2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 175 ° C;

6-nitro-2,2-dimethyl-3- (izobutánamidö) methyl-4- (2-oxo-

1.2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 180 ° C; and

6-cyano-2,2-dimethyl-3- (acetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 160 ° C.

C) A process for the preparation of compounds of formula I wherein R 1 and R ^{2 are} methyl, R ⁸ and R ^{8 are} hydrogen, R ^{8 is} -COR ⁴² and R ⁸ , R ⁴ , R ⁸ and R ¹² are variable

Proceed as above, optionally using 6-trifluoromethyl-2,2-dimethyl-3- (aminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-. benzopyran is replaced by a suitable compound of formula (15) or (IA), for example as described in Reference Example 17 or Example 1 or 2, and acetyl chloride is replaced by a corresponding acid halide of formula R ⁴² COCl or R ²² COBr , the latter having a lower alkyl group, and

Following the procedure of Example 6A, the compounds of formula (I) referred to in Example 4, wherein R 1 - ² is lower alkyl, were prepared.

Example 7

Alternate preparation of (I) compounds wherein R ⁸ is hydroxy and R @ ⁸ COR ^ ²

-1041 9, wherein R is lower alkyl

A) ____ Preparation of compound (I) wherein R ^J is trifluoromethyl, R ^x and R is methyl, R5 and R6 are hydrogen, R ⁴ 2-oxo-1,2 ~ dihydropyridin-1-yl group, R is hydroxy and R is -COR ^14, wherein R * * ^{2 is} methyl

0.48 g (1.31 mmol) of 6- (trifluoromethyl) -2,2-dimethyl-3- (hydroxyaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) A solution of 2 H -1-benzopyran in 13 mL of dichloromethane was cooled to 0 ° C and triethylamine (0.18 mL, 1.31 mmol) and acetyl chloride (0.1 mL, 1.31 mmol) were added and the mixture was stirred at room temperature for 1 h. Stir at 0 ° C for 45 minutes. The mixture was diluted with water, the organic layer was separated, washed with water, dried and evaporated. The crude product was chromatographed on silica gel eluting with dichloromethane: methanol (95: 5, v / v). The separated oily material was crystallized from ether to give 6- (trifluoromethyl) -2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) 0.24 g. ), -2H-1-benzopyran, m.p. 188 ° C.

B) ___ Preparation of compounds of formula I wherein R 1 - and R ^{2 are} methyl and R 4 is hydrogen, R ⁴ p

2-oxo-1,2-dihydropyridin-1-yl; R is hydroxy

Q 1 9

R ^is -COR

9, R is alkyl and R ³ variable

The same procedure was followed except that 6- (trifluoromethyl) -2,2-dimethyl-3- (hydroxyaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) was used. -2H-l-benzopyran is a suitable,

-105 is replaced, for example, by a compound of formula IA prepared as described in Example 1 or 2 and optionally acetyl chloride by a suitable acid halide R 1 COd, the latter of which is a lower alkyl group and following the procedure of Example 7A). the following compounds of the formula I are prepared:

6-nitro-2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 245 ° C;

6-cyano-2,2-dimethyl-3- (N-acetamidomethyl) -4- (2-oxo-l, 2-dihydro-l-yl) -2H-1-benzopyran, mp. 220 ° C;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 152 ° C;

6-bromo-2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 218 ° C;

6-chloro-2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 191 ° C;

2,2-dimethyl-3- (N-hydroxyacetamido) methyl-4- (2-oxo-

1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 184 ° C; and 6-bromo-2,2-dimethyl-3- (N-hydroxypropionamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 218 ° C.

C) ___ Preparation of compounds of formula I wherein both methyl and Εθ are hydrogen,

-C0r12 group of formula and R ^4, is variable and

The same procedure is followed except that 6- (trifluoromethyl) -2,2-dimethyl-3- (hydroxyaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) may be used. ) -2H-1-benzopyran in a suitable manner, for example as described in Examples 1 or 2

-106-

compound of the acetyl chloride was replaced with a suitable R ² COC1 or R @ ³² Cobra its acid halide, prepared in (IA) following the R ^XI appropriate lower alkyl procedure of EXAMPLE wherein R ^ ² is lower alkyl, and 7) containing the compounds of formula I mentioned in Example 5.

8.példa

Preparation of compound (I) of formula wherein R ⁹ groups of formula ⁹ ^ -CPoR

A) Preparation of a compound of formula (I) wherein R ^{3 is} nitro and R ^{2 is} methyl, R 1 and R 4 are hydrogen, R 2-oxo-1,2-dihydropyridin-1-yl, R ^{9 is} hydrogen. and R ^{9 is} -CO ² R 4 - ⁹ , wherein R ^{9 is} methyl

0.53 g (1.53 mmol) of 6-nitro-2,2-dimethyl-3- (aminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1- benzopyran and

To a solution of triethylamine (0.25 mL, 1.80 mmol) in dichloromethane (10 mL) was added methyl chloroformate (0.14 mL, 1.80 mmol) at room temperature. The solution was stirred for 2 hours and then diluted with water. The organic layer was separated, dried and evaporated, and the crude product was crystallized from ether. The crystalline material was then purified by chromatography on silica gel using a 20:80 by volume mixture of acetone and dichloromethane as the eluent, yielding 0.33 g of 6-nitro-2,2-dimethyl-3r (methoxycarbonylaminomethyl) -4- (2-oxo- 1,2-Dihydropyridin-1-yl) -2H-1-benzopyran is isolated, m.p. 199 ° C.

B) Preparation of a compound of formula (I).

-107- in which both R ^{2 is} methyl, and R 1 is hydrogen, R ^{2 is} bromo, R is hydroxy, and R 1 -CPo R 4 are in which R 1 -θ is methyl.

The procedure is the same as described above, except that 6-nitro-2,2-dimethyl-3- (aminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1- benzopyran is replaced by a suitable compound of formula IA, for example, as described in Example 2, and following the procedure of Example 8A, the following compound of formula I is prepared:

6-bromo-2,2-dimethyl-3- (methoxycarbonylaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 229 ° C.

C) ___ Preparation of compounds of formula I wherein R 1 and R ^{2 are} methyl, R 1 and R ^{2 are} hydrogen, R 1 -CO 8 R ¹⁰ and R ² , R 1, R ² , r ⁹ and R 6 are

The procedure is the same as described above, except that 6-nitro-2,2-dimethyl-3- (aminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1- benzopyran with a suitable compound of formula (15) or (IA), for example as described in Reference Example 17 or Example 1 or 2, and optionally methyl chloroformate with a lower alkyl group of formula 01002Κ-θ. is replaced with chloroformate and following the procedure of Example 8A, the following compounds of formula I are prepared:

6-nitro-2,2-dimethyl-3- (ethoxycarbonylmethyl-amino-methyl) -4- (2-oxo-l, 2-dihydro-l-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (N-methylmethoxycarbonylaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

-1086-cyano-2,2-dimethyl-3- (methoxycarbonyl-amino) methyl-4- (2-oxo-1,2-dihydropyridine-l-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (ethoxycarbonylmethyl-amino-methyl) -4- (2-oxo-l, 2-dihydro-l-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N-methylmethoxycarbonylaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (methoxycarbonylaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (ethoxycarbonylamino) methyl-4- (2-oxo-l, 2-dihydro-l-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methylmethoxycarbonylaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) 2H-1-benzopyran ;

6- (pentafluoroethyl) -2,2-dimethyl-3- (methoxycarbonylaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (ethoxycarbonylaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-methylmethoxycarbonylaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-benzopyran;

6-nitro-2,2-dimethyl-3- (methoxycarbonyl-amino-methyl) -4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (ethoxycarbonylmethyl-amino-methyl) -4- (2-oxo-pyrrolidin-l-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (N-methoxycarbonyl-amino) -1094- (2-oxopyrrolidin-l-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (methoxycarbonyl-amino-methyl) -4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (ethoxycarbonylaminomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N-methoxycarbonyl-amino) 4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (methoxycarbonylamino) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (ethoxycarbonylamino) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

- (trifluoromethyl) -2,2-dimethyl-3- (N-methylmethoxycarbonylaminomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (methoxycarbonylamino) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (ethoxycarbonylamino) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-methyl-methoxycarbonylamino) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (methoxycarbonyl-amino) -4 (l-oxoisoindolin-2-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (ethoxycarbonylaminomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (N-methoxycarbonyl-amino) -4- (l-oxo-isoindolin-2-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (methoxycarbonyl-amino) -4 (l-oxoisoindolin-2-yl) -2H-l-benzopyran;

-1106-cyano-2,2-dimethyl-3- (ethoxycarbonylmethyl-amino) -4 (1-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (N-methoxycarbonyl-amino) -4- (l-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (methoxycarbonylamino) methyl-4- (l-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (ethoxycarbonylamino) methyl-4- (l-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methyl-methoxycarbonylamino) methyl-4- (l-oxo-isoindolin-2-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (methoxycarbonylamino) methyl-4- (l-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (ethoxycarbonylamino) methyl-4- (1-oxo-isoindolin-2-yl) -2H-1-benzopyran; and

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-methylmethoxycarbonylaminomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran.

example 9

Preparation of compounds of formula (I) wherein -CONHR ⁴ is a group

A) Preparation of ____ (I) compound in which a nitro group, R ⁴ and R = methyl group, and hydrogen atom and Εθ -CONHR ^{4 'radical,} an ethyl group, R ^4'

6-Nitro-2,2-dimethyl-3- (aminomethyl) 4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran (0.5 g, 1.53 mmol) A solution of dichloromethane (10 mL) was stirred at room temperature with ethyl isocyanate (0.12 mL, 1.53 mmol) for 2 hours. The mixture • ·· ·· ·

To this is added water, the organic phase is separated, dried and evaporated. The crude product was chromatographed on silica gel eluting with 95: 5 dichloromethane: methanol to give 0.34 g of 6-nitro-2,2-dimethyl-3- (N'ethylureido-methyl) -4- (2 of oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran, m.p. 197 ° C.

B) Preparation of a compound of general formula (I) wherein R ^{8 is} bromo, R 1 and R ^{2 are} methyl, R ⁸ and R ^{8 are} hydrogen, R ^{4 is} 2-oxo-1,2-dihydropyridin-1-yl, R ⁸

Λ-in is hydroxy and R is -CONHR ¹⁶ where R R is ² hydrogen

0.300 g (0.0795 mol) of 6-bromo-2,2-dimethyl-3- (hydroxyaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran with tetrahydrofuran Trimethylsilyl isocyanate (0.22 mL, 0.18 g, 0.0016 mol) was added dropwise at room temperature under nitrogen and the reaction mixture was stirred overnight at room temperature and water and dichloromethane were added. The organic layer was separated, dried and evaporated. The crude product was chromatographed on silica gel eluting with dichloromethane: methanol (90:10 v / v) to give 0.24 g (72%) of 6-bromo

2,2-Dimethyl-3- (N-hydroxy-urea-methyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran is isolated, m.p. melted.

C) Preparation of compounds of general formula (I) wherein R 1 and R ^{2 are} methyl, R ⁸ and R ^{8 are} hydrogen, R ^{8 is} -CONHR-12, and R ⁸ , R ⁸ , R ⁸ and R ¹² are variable

The procedure is similar to that described above, but in some cases, 6-nitro-2,2-dimethyl-3- (aminomethyl) ) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran is prepared in a suitable manner, for example as described in Reference Example 17 or Example 1 or 2, or A compound of formula IA, and optionally ethyl isocyanate, is substituted with an appropriate lower alkyl isocyanate of formula R ² NCO, and following the procedure of Example 9A, the following compounds of formula I are prepared:

6-nitro-2,2-dimethyl-3- (N'-methylureido) methyl-4- (2-oxo-

1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3 - [(N-methyl-N'-ethyl-ureido) -methyl] -4- (2-oxo-l, 2-dihydro-l-yl) -2H-1- benzopyran;

6-cyano-2,2-dimethyl-3- (N'-methylureido) methyl-4- (2-oxo-

1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N'-ethylureido) methyl-4- (2-oxo-

1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3 - [(N-methyl-N'-ethyl-ureido) -methyl] -4- (2-oxo-l, 2-dihydro-l-yl) -2H-1- benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N'-methyl-ureidomethyl) -4- (2-oxo-1,2-dihydropyridine-l-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N'-ethyl-ureidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3 - [(N-methyl-N'-ethylureido) methyl] -4- (2-oxo-2-dihidro.piridin-l-yl) -2H-l-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (6'-methyl-ureidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N'-ethyl-ureidomethyl) -4- (2-oxo-l, 2-dihydro-l-yl) -2H-l-benzopyran;

· <·· · «« «·« «• · A *» * · »· · • · ♦ * · · * · * · ♦♦ *« «> <« »«

-1136- (pentafluoroethyl) -2,2-dimethyl-3- (N-methyl-N'-ethylureido-methyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H- 1-benzopyran;

6-nitro-2,2-dimethyl-3- (N'-methylureido) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (N'-ethyl-ureido-methyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (N-methyl-N'-ethylureido) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (N'-methylureido) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (N'-ethyl-ureido-methyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N-methyl-N'-ethylureido) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N'-methyl-ureidomethyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N'-ethyl-ureidomethyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methyl-N'-ethylureido) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N'-methyl-ureidomethyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

6- (pentafluoro-ethyl) -3- (N'-ethyl-ureido-methyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

6- (pentafluoro-ethyl) -2,2-dimethyl-3- (N-methyl-N'-ethyl-urea-methyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (N'-methyl-ureido-methyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

• · · ·· «· 4 · · ··« * .4 • · »4 · • ♦ 4 t

6-nitro-2,2-dimethyl-3- (N'-ethylureido) methyl-4- (1-oxoisoindoline-2-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (N-methyl-N'-ethylureido) methyl-4- (l-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (N'-methyl-ureido-methyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N'-ethylureido) methyl-4- (1-oxoisoindoline-2-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N-methyl-N'-ethylureido) methyl-4- (l-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methylureaidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N'-ethyl-ureidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methyl-N'-ethylureido) methyl-4- (1-oxo-isoindolin-2-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N'-methyl-ureidomethyl) -4- (1-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6- (pentafluoroethyl) -3- (N'-ethylureido) methyl-4- (1-oxoisoindoline-2-yl) -2H-1-benzopyran; and

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-methyl-N'-ethylureido-methyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran.

10.példa

Preparation of compounds of formula (I)

in R ⁹ -CSNHR ¹² a group of the general formula A) Yes (I) Preparation of a compound of the formula. wherein R R nitro , R ⁴ and R ^{2 are} methyl, R ⁸ and R® hydrogen, R ⁴ 2-oxo- 2-dihydropyridin-1-yl, R ⁹

· * · *

-115z Q 19 9 * * H and R ^a -CSNHR ¹⁶ where R ^{42 is} methyl

6-Nitro-2,2-dimethyl-3- (aminomethyl) 4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran (0.5 g, 1.53 mmol) and a solution of 0.11 g (1.5 mmol) of methyl isothiocyanate in 10 ml of dichloromethane were stirred at room temperature for 26 hours. The solvent was evaporated and the residue was washed with diethyl ether to give 0.34 g of 6-nitro-2,2-dimethyl-3- (N'-methylthioureidemethyl) -4- (2-oxo)

1,2-dihydropyridin-1-yl) -2H-1-benzopyran is obtained, m.p. 225 ° C.

B) Preparation _____ A compound of formula (I) wherein R ² a bromine atom, R ⁴ and R ² is methyl, R ² and R ² is hydrogen, R ⁴ 2-oxo-l, 2-dihydro-l-yl group, R ² nio hydroxy and R is a general formula CSNHR,

2 in which R ¹ * ^{1 is} hydrogen

Trimethylsilyl isothiocyanate is added dropwise at room temperature to a solution of 6-bromo-2,2-dimethyl-3- (hydroxyaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran at room temperature. . The reaction mixture was stirred at room temperature for 2 hours. It is then diluted with water, the organic layer is separated, dried and evaporated. The residue was triturated with diethyl ether to give 6-bromo-2,2-dimethyl-3- (N-hydroxy thioureidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) 0.18 g. 2H-1-benzopyran is obtained, m.p. 219 ° C.

C) ___ Preparation of compounds of formula I wherein R ⁴ and R ^{2 are} methyl, R ² and R ^{2 are} hydrogen, R ^{2 is} -CSNHR ⁴² and R ² , R ⁴ , R ² and R ⁴²

I ·· * · ···· e · «• 5 · *« ·· «<

• ·· φ · 4 · ·

Its meaning is variable

The procedure is the same as described above, except that 6-nitro-2,2-dimethyl-3- (aminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1- benzopyran with a suitable compound of formula (15) or (IA), for example as described in Reference Example 17 or Example 1 or 2, and optionally methyl isothiocyanate with a suitable lower alkyl group of formula R 1 NCS with thiocyanate and following the procedure of Example 10A to give the following compounds of formula (I):

Six-nitro-2,2-dimethyl-3- (N'-methyl-thioureido) methyl-4- (2-oxo-1,2-dihydropyridin-l-yl) -2H-l-benzopyran;

6-nitro-2,2-dimethyl-3- (N-methyl-N'-ethyl tioureidometil) -4- (2-oxo-l, 2-dihydro-l-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N'-methyl-thioureido) methyl-4- (2-oxo-1,2-dihydropyridin-l-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (N'-ethyl-thioureido) methyl-4- (2-oxo-1,2-dihydropyridin-l-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N-methyl-N'-ethylthioureidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N'-methylthioureidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) - * 2H-1-benzopyran ;

6- (trifluoromethyl) -2,2-dimethyl-3- (6'-ethylthioureidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methyl-N'-etiltioureido) methyl-4- (2-oxo-l, 2-dihydro-l-yl) -2H-benzopyran ;

6- (Pentafluoroethyl) -2,2-dimethyl-3- (N'-methylthioureido · · · · · · · · ·

117 methyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N'-ethyl-tioureidometil) -4- (2-oxo-l, 2-dihydro-l-yl) -2H-1-benzopyran;

6- (Pentafluoroethyl) -2,2-dimethyl-3- (N-methyl-N'-ethylthioureidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran ;

6-nitro-2,2-dimethyl-3- (N'-methyl-thioureido) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (N'-ethyl-thioureido) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (N-methyl-N '-ethylthioureidomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N'-methyl-thioureido) -4 (2-oxopyrrolidin-l-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N'-ethyl-thioureido-ylmethyl) -4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N-methyl-N'-ethylthioureidomethyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N'-methyl-tioureidometil) -4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N'-ethylthioureidomethyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methyl-N'-etiltioureido) methyl-4- (2-oxo-pyrrolidin-l-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N'-methylthioureidomethyl) -4- (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (6'-ethylthioureidomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-methyl-N'-ethyl) · · ·

-118tioureidő) methyl-4- (2-oxo-pyrrolidin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (N'-methyl-thioureido) methyl-4- (1-oxo-isoindolin-2-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (N'-ethyl-thioureido) methyl-4- (1-oxo-isoindolin-2-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (N-methyl-N'-ethylthioureidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6-cyano-2,2-dimethyl-3- (N'-methyl-thioureido meti1) -4- (l-oxo-isoindolin-2-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (N'-ethyl-thioureido) -4 (l-oxoisoindolin-2-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (N-methyl-N'-ethylthioureidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (6'-methylthioureidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N'-ethylthioureidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (N-methyl-N'-etiltioureido) methyl-4- (l-oxo-isoindolin-2-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (6'-methylthioureidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (N'-ethylthioureidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran; and

6- (pentafluoroethyl) -2,2-dimethyl-3- (N-methyl-N'-etiltioureido) methyl-4- (1-oxo-isoindolin-2-yl) -2H-1-benzopyran.

11.példa

Preparation of compounds of formula I wherein R ^{3 is} -SO ² R ⁴

A) Preparation of a compound of the formula I

Β ^J nitrocsoport.R in R ¹ and R ^h is methyl, R ° and R ° is hydrogen, R ⁴ 2-oxo-l, 2-dihydro-l-yl, ^R8 is hydrogen and ^R8 -SC -119ο 12 r R ^{48 is} R ⁴⁸ wherein R ^{48 is} methyl

6-Nitro-2,2-dimethyl-3- (aminomethyl) 4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran (0.43 g, 1.31 mmol) and to a solution of triethylamine (0.22 mL, 1.58 mmol) in dichloromethane (15 mL) were added methanesulfonyl chloride (0.12 mL, 1.55 mmol). The mixture was stirred at room temperature for 4 hours and then diluted with water. The organic layer was separated and concentrated under reduced pressure. The residue was washed with diethyl ether to give 0.3 g of 6-nitro-2,2-dimethyl-3- (methanesulfonamidomethyl) -4- (2-oxo)

1,2-dihydropyridin-1-yl) -2H-1-benzopyran is obtained, m.p. 195 ° C.

B) ___ Preparation of compounds of formula I wherein R ⁴ and R ^{2 are} methyl, R ⁸ and R ^{8 are} hydrogen, R ^{8 is} -SO ¹⁰ R ¹⁰ , and R ⁸ , R ⁴ , R ⁸ and R ⁴⁸ are variable

The procedure is the same as described above, except that 6-nitro-2,2-dimethyl-3- (aminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1- benzopyran with a suitable compound of formula (15) or (IA), for example as described in Reference Example 17 or Example 1 or 2, and optionally R ⁴⁸ SO 2 Cl or methanesulfonyl chloride having an R ⁴⁸ lower alkyl group; R ^{48 is} replaced by a compound of formula SO 2 Br and following the procedure of Example 11A, the following compounds of formula I are obtained:

6-cyano-2,2-dimethyl-3- (methanesulfonamido) methyl-4- (2-120οχο-1,2-dihydropyridin-l-yl) -2Η-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (methanesulfonamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

6 (pentafluoroethyl) -2,2-dimethyl-3- (metánszulfonamidometil) -4- (2-oxo-l, 2-dihydro-l-yl) -2H-1-benzopyran; 6-nitro-2,2-dimethyl-3- (methanesulfonamido) -4 (2-oxopyrrolidin-l-yl) -2H-l-benzopyran;

6-cyano-2,2-dimethyl-3- (methanesulfonamido) -4 (2-oxopyrrolidin-l-yl) -2H-1-benzopyran;

6- (trifluoromethyl) -2,2-dimethyl-3- (methanesulfonamidomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6- (pentafluoroethyl) -2,2-dimethyl-3- (methanesulfonamidomethyl) -4- (2-oxopyrrolidin-1-yl) -2H-1-benzopyran;

6-nitro-2,2-dimethyl-3- (methanesulfonamido) -4 (1-oxo-isoindolin-2-yl) -2H-benzopyran;

6-cyano-2,2-dimethyl-3- (methanesulfonamido) -4 (l-oxoisoindolin-2-yl) -2H-l-benzopyran; 6- (trifluoromethyl) -2,2-dimethyl-3- (methanesulfonamidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran; and 6- (pentafluoroethyl) -2,2-dimethyl-3- (methanesulfonamidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran.

EXAMPLE 12

Alternative process for the preparation of compounds of Formula I wherein R ^{9 is} -CO 0 R 4 ⁹ , -CONR ³ -C ² R ² or -CO ^{2 2}

A) ____ Preparation of a compound of formula I wherein R ^{3 is} nitro, R 1 and R ^{2 are} methyl, R 6 and R ^{9 are} hydrogen, R 2 -oxo-1,2-dihydropyridin-1-yl, R ⁹ hydrogen; and R ^{9 is} -COR ² ;

-121trifluor-methyl

6-Nitro-2,2-dimethyl-3-hydroxy-3,4-dihydro-3- (trifluoroacetamidomethyl) -4- (2-oxo-1,2-dihydropyridine, 0.5 g, 1.13 mmol) To a solution of -1-yl) -2H-1-benzopyran in 20 ml of tetrahydrofuran was added 0.034 g (1.13 mmol) of 80% sodium hydride and the mixture was refluxed for 1 hour. The solution was cooled and water and ethyl acetate were added. The organic layer was separated and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with a 95: 5 mixture of dichloromethane and acetone. 0.13 g of 6-nitro-2,2-dimethyl-3- (trifluoroacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran are isolated. mp 189 ° C.

B) ___ Preparation of a compound of formula (I) wherein R * and methyl, R 4 and hydrogen are R 9 -CO 2 R 10 <-CONR 1 -R 4 or -COR 4 and R 1, R 4, R 6, R 6, rH and R6 are variable

The same procedure as above, except that 6-nitro-2,2-dimethyl-3-hydroxy-3,4-dihydro-3- (trifluoroacetamidomethyl) -4- (2-oxo-1,2 -dihydropyridin-1-yl) 2H-1-benzopyran is replaced by a suitable compound of formula (19), for example, as described in Reference Example 21, and following the procedure of Example 12A, the compound (I) mentioned in Examples 1-9. Compounds of formula Ia are obtained.

13.példa

Preparation of compounds of formula (I) wherein R 1 - 2-oxo-pyrrolidin-1-yl or 1-oxo-isoindolin-2

-122I and -CONR ¹ · or -COR · ¹ →

A) Preparation of a compound of formula (I) wherein nitro, R ¹ and R 4 are methyl, R 1 and R 4 are hydrogen, R 2 -oxopyrrolidin-1-yl, R 1 is hydrogen and -COR 12 wherein R * is methyl

6-Nitro-3- (acetamidomethyl) -3,4-dihydro-3,4-epoxy-2,2-dimethyl-2H-1-benzopyran (0.5 g, 1.72 mmol), 0.3 g (3 g). (48 mmol) of 2-pyrrolidinone and 0.1 mL of Triton B (40% in ethanol) in 10 mL of dioxane was heated at 50 for 18 h. Water and ethyl acetate were added and the organic layer was separated and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with dichloromethane: methanol (95: 5, v / v) to give 6-nitro-2,2-dimethyl-3- (acetamidomethyl) -4- (2-oxopyrrolidine, 0.14 g). -1-yl) -2H-1-benzopyran, m.p. 205 ° C.

B) Preparation of a compound of formula (I) wherein nitro, R ¹ and R 4 are methyl, and R 4 is hydrogen, R 1 -oxoisoindolin-2-yl, R 0 is hydrogen, and -CO 2 R 2 is wherein R ^{1 is} methyl

In the same manner as above, the 2-pyrrolidinone is replaced by 1-oxoisoindole and following the procedure of Example 13A, the following compound of formula I is prepared:

6-nitro-2,2-dimethyl-3- (acetamidomethyl) -4- (1-oxoisoindolin-2-yl) -2H-1-benzopyran, m.p. 220 ° C.

-123-

C) ___ Preparation of compounds of formula (I) wherein R 1 and R ^{2 are} methyl, R ² and R ^{2 are} hydrogen, R 2 -oxopyrrolidin-1-yl or 1-oxoisoindolin-2-yl R9 -CC ^ R ^ O ^ -CONRÜrI ² or -COR ² group of formula and R ^2, R ^, ^R2, R ^ θ, R j * and R ^ ² is variable

The same procedure is followed except that 6-nitro-2,2-dimethyl-3-hydroxy-3,4-dihydro-3- (trifluoroacetanimidomethyl) -4- (2-oxo-1,2-dihydropyridine) may be used. -1-yl) -2H-1-benzopyran is replaced by a suitable compound of formula (18), for example, as described in Reference Example 20, and following steps 1 to 9 following procedure 13A). The compounds of formula (I) mentioned in Example 3a are obtained.

Example 14 Conversion of compounds of formula I into salts

A) 0.44 g (1.18 mmol) of 6-nitro-2,2-dimethyl-3- (2-hydroxyethylaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) ) To a solution of 2H-1-benzopyran in diethyl ether was added an excess of 2M hydrochloric acid in ethanol and the resulting precipitate was collected by filtration to give 0.36 g of 6-nitro-2,2-dimethyl-3- (2-hydroxyethylamino) methyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran hydrochloride, m.p. 225 ° C.

B) Proceed as above, except that the 6-nitro-

2,2-Dimethyl-3- (2-hydroxyethylaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran is a corresponding compound of formula I base to give the corresponding hydrochloride salt.

Example 15

This example is an oral administration of general formula (I)

A compound of formula -124 or a pharmaceutically acceptable salt thereof, such as 6-nitro-2,2-dimethyl-3- (acetamidomethyl) -4- (2-oxo)

Illustrates the preparation of a pharmaceutical composition comprising 1,2-dihydropyridin-1-yl) -2H-1-benzopyran:

A) Components % W / w A compound of formula (I) 20.0 Lactose 79.5 Magnesium stearate 0.5

The above components are mixed and 100 mg portions of the mixture are filled into hard gelatin capsules; one capsule approximately corresponds to a whole daily dose.

B) Components % W / w A compound of formula (I) 20.0 Magnesium stearate 0.9 Starch 8.6 Lactose 69.6 PVP (polyvinylpyrrolidone) 0.9

With the exception of magnesium stearate, the above components are mixed and granulated with water. The formulation is then dried, mixed with magnesium stearate and compressed into tablets using a suitable tabletting machine.

C) Components

A compound of formula (I) 0.1 g propylene 20.0 g Polyethylene glycol 400 20.0 g Polysorbate 80 1.0 g Filled with water To 100 ml

The compound of formula (I) was dissolved in propylene glycol, polyethylene glycol 400 and polysorbate 80.

With stirring, enough water was added to obtain 100 ml of solution, which was then filtered and bottled.

D) Components 20% w / w Compound I

Peanut oil 78.0

Span 60 2.0

The above components are melted, mixed and filled into soft elastic capsules.

Example 16

This example provides a parenteral compound of formula (I) or a pharmaceutically acceptable salt thereof, such as 6-nitro-2,2-dimethyl-3- (N-hydroxyacetamidomethyl) 4- (2-oxo-1,2- discloses the preparation of a pharmaceutical composition comprising dihydropyridin-1-yl) -2H-1-benzopyran:

Components Compound of Formula I 0.02 g

propylene 20.0 g Polyethylene glycol 400 20.0 g Polysorbate 80 1.0 g

Make up to 100 ml with 0.9% sodium chloride solution.

The compound of formula I, for example 6-nitro-

2,2-Dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran in propylene glycol, polyethylene glycol 400 and polysorbate 80 in. While stirring, 0.9% sodium chloride solution was added to give 100 mL of an intravenous solution, which was then passed through a 0.2 micron membrane filter and packaged under sterile conditions.

-126-

17.példa

This example is a suppository compound of formula (I) or a pharmaceutically acceptable salt thereof such as 6-cyano.

The preparation of a pharmaceutical composition comprising 2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran illustrates:

Components of the formula I are 1.0% w / w

Polyethylene glycol 100074.5

Polyethylene glycol 400024.5

The components are melted in a steam bath and mixed and then poured into molds of a total weight of 2.5 g.

18.példa

This example provides an infusion of a compound of Formula I or a pharmaceutically acceptable salt thereof, such as 6- (pentafluoroethyl) -2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1). 2-Dihydropyridin-1-yl) -2H-1-benzopyran.

Components by weight /% by weight

Micronized compound of formula I 1.0

Micronized lactose

99.0

The components are ground, mixed and filled into a blower fitted with a metering pump.

19.példa

This example is a spray of a compound of formula (I) or a pharmaceutically acceptable salt thereof, such as 6-nitro-2,2-dimethyl-3- (formamidomethyl) -4- (2-oxo)

Discloses the preparation of a pharmaceutical composition comprising 1,2-dihydropyridin-1-yl) -2H-1-benzopyran:

-127-

Components are compounds of formula (I)

Water

Ethanol w / w

0,005

89.995

10,000

The compound of formula (I) is dissolved in ethanol and water. The composition is then filled into a device fitted with a metering pump.

Example 20

With this example, an aerosolized compound of formula (I) or a pharmaceutically acceptable salt thereof, such as 6- (trifluoromethyl) -2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2- preparation of a pharmaceutical composition containing oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran:

The components are% w / w of the compound of formula I 0.10

Carrier gas 11 / 1298.90

Olajsav1,00

The compound of formula (I) is dispersed in oleic acid and vehicle gas. The resulting mixture is then filled into an aerosol container with a metering valve.

Example 21

This example is a topically applied ophthalmic compound of formula I or a pharmaceutically acceptable salt thereof, such as 6-cyano-2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1), Discloses the preparation of a pharmaceutical composition comprising 2-dihydropyridin-1-yl) -2H-1-benzopyran: Components of the Formula I 0.10 g.

-128Benzalkonium chloride 0.01 g Polyethylene glycol 400 5.00 g Glycerol 5.00 g NaH ₂ PO ₄ 1.00 g Na ₂ HPO ₄ 1.00 g NaOH q. s. p.

Supplemented with 0.9% sodium chloride solution to 100 ml of benzalkonium chloride, polyethylene glycol 400,

NaH ₂ PO ₄ and Na ₂ HPO ₄ were dissolved in 0.9% sodium chloride solution. The compound of formula I, e.g., 6-cyano-2,2-dimethyl-3- (N-hydroxyacetamethylmethyl) -4- (2-oxo)

1,2-Dihydropyridin-1-yl) -2H-1-benzopyran is added to the solution. The solution was neutralized with aqueous sodium hydroxide solution to obtain an isotonic pH. The solution is filtered through a 0.2 micron membrane strainer and filled under sterile conditions into suitable containers and sterilized by autoclaving at 120 ° C.

22.példa

Determination of smooth muscle relaxant properties (in vitro)

The smooth muscle relaxant properties of the compounds were evaluated in vitro using pre-contracted vasculature with appropriate spasmogenic material as follows:

A) Rats were sacrificed by head-to-head and the aorta was rapidly removed from the animals. The tissues were cleaned of connective tissue, and the endothelial cells were removed by gentle rubbing with tweezers and the aorta was cut into rings. These strips were then placed in physiological Krebs solution at 37 ° C and at a tensile stress of 2 g, the solution consisted of 95% oxygen and 5% carbon dioxide.

-129 gas mixture was passed through. Prolonged contractions with potassium chloride (20 mM final bath concentration) were induced. The contractile force of the muscle strips is recorded isometrically. The test compounds were added in cumulatively increasing concentrations (10 ^-4 θ - 10 ^- 1 M) in water or a mixture of water and a few drops of Tween in 80% or 1% alcohol. The maximum reduction in potassium chloride induced voltage was at different concentrations of compounds. Results for compounds of Formula I were expressed as pICgQ (negative logarithm of the concentration of compound capable of inhibiting 50% potassium chloride induced contraction). The results are summarized in the following table:

Compound £ IC ₅₀ 1 8.72 2 8.28 3 7.99 4 8.90 5 7.46 6 7.48 7 8.80 8 8.80

Compound 1: 6-bromo-2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) 2H-1-benzopyran;

• · · · «

......; . · -130- 2.vegyület: 6-chloro-2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) 2H-1-benzopyran; 3.vegyület: 6-bromo-2,2-dimethyl-3- (N-hydroxypropionamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran; 4.vegyület: 6-nitro-2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4 - ((2-oxo-1,2-dihydropyridin-1-yl) 2H-1-benzopyran; 5.vegyület: 6-Nitro-2,2-dimethyl-3- (acetamidomethyl) -4 (2-oxo-l, 2-dihydro-l-yl) -2H-1-benzopyran; 6.vegyület: 6-nitro-2,2-dimethyl-3- (formamido) methyl-4- (2-oxo-l, 2-dihydro-l-yl) -2H-1-benzo- pyran; 7.vegyület: 6- (trifluoromethyl) -2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -N-oxo-1H-dihydropyridin-1-yl) -2H-1-benzopyran; 8.vegyület: 6- (pentafluoroethyl) -2,2-dimethyl-3- (N-hidroxiacetárnido) methyl-4- (2-oxo-l, 2-dihydro-l-yl) -2H-l-benzopyran. They are Compounds of formula I in this

study showed positive smooth muscle relaxant properties.

B) In a similar experiment, compounds of formula I did not loosen aortic rings contracted with 40 mM potassium chloride, and these results are consistent with a physiological mechanism involving the activation of potassium channel.

: * · *:

Example -13123

Interaction with potassium channel antagonist glibenclamide

Endothelial-cleaned aortic rings from 250-300 g Sprague-Dawley rats were suspended in Krebs bicarbonate solution at 37 ° C and resting at 2 g resting tension at 37 ° C. For the assay, J. Pharm. Exp. Ther. 248: 1261-1268 (1989)]. Contraction of the preparations was induced by increasing the potassium ion concentration by adding potassium chloride to the bath to a concentration of 20 mM. Once the contraction response was stabilized, glibenclamide, known as potassium channel antagonist, or the appropriate vehicle (control) was added to the bath medium and the tension force recorded over the next 30 minutes. After this incubation period, the compounds of the formula I to be tested were added in increasing cumulative concentrations to obtain concentration-relaxation curves. At each successive concentration, the maximum was expected to be reached before the next portion of the test substance was added. Groups of 4-6 preparations were used for each treatment.

The concentration of compounds required to elicit a relaxing effect equal to 50% of the maximum response is the PIC5Q (where 100% represents the return to baseline before contraction) in the presence or absence of glibenclamide, and

(CR) was calculated. For various concentrations of glibenclamide, the antagonist affinity constant (pKg) is described in RFFurchgott, The Classification of Adrenoceptors (Adrenergic Receptor), 1972, 33, 282. -335).

Glibenclamide has a pKg of 6- (trifluoromethyl) -2,2-dimethyl-3- (N-hydroxyacetamido) methyl-4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-. using benzopyran as a relaxant resulted in 7.63.

In this assay, the smooth muscle relaxant effect of the compounds of formula I was antagonized by glibenclamide, which means that the compounds exert an activating effect on the potassium channel.

24.példa

Determination of the antihypertensive effect in vivo

The antihypertensive activity of the compounds of formula (I) was determined in Iffa Credo, spontaneously hypertensive rats, aged 18-20 weeks. Rats were anesthetized by intraperitoneal administration of 50 mg / kg pentobarbital and a catheter was inserted into the descending aorta through the femoral artery of the animals. The catheter was inserted at the back of the neck and sealed with a needle. After surgery, rats were housed individually and 1-3 days later, pulsed aortic blood pressure was directly measured in groups of 4 to 8 wake animals using a Statham P50 pressure transducer coupled to a Gould S8000 recorder. Higher than 145mmHg

Blood-pressure rats were considered to be spontaneously hypertensive -133 * ··· * · ♦ 044 * · · «· ♦ *» «·.

Test compounds for oral administration are 2%

Tween 80 was suspended. The control group received vehicle only (0.5 ml / kg p.o.). Cardiovascular parameters were recorded at 15, 30, 45, and 60 minutes, followed by 7 hours every hour, and 24 hours after administration. Maximum changes in systolic, diastolic and mean blood pressure as well as changes in heart rate were measured. Percent changes in blood pressure and heart rate from baseline and vehicle-treated time controls were calculated. For the duration of the antihypertensive effect, the time during which the blood pressure value was significantly lower than that of the vehicle treated group was taken into account. The results obtained after oral administration of 300 micrograms / kg of test compounds are summarized in the following table:

Compound Peak Effect (%) First -22.0 + 4.0 Second -52.0 + 1.0 3. -31.1 + 4.9

Compound 1: 6-bromo-2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) 2H-1-benzopyran;

Compound 2: 6-nitro-2,2-dimethyl-3- (N-hydroxyacetamido-134-

methyl) -4- (2-oxo-l, 2-dihydro-l-yl)

2H-l-benzopyran;

Compound 3: 6-nitro-2,2-dimethyl-3- (acetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran.

Compounds of formula (I) showed positive antihypertensive activity in this assay.

25.példa

Histamine-induced bronchospasm in anesthetized guinea pigs (in vivo determination)

Assays were performed on 330-450 g male guinea pigs (Cob.lab.) According to a modified version of Dixon and Brodie (1). The animals were injected intravenously with 1-2 mg / kg of ethyl carbamate in two separate injections (i.p.) and received 1 mg / kg of gallamine. A cannula was inserted into the trachea and connected to a small animal (Harvard) ventilator to maintain the animals' artificial respiration. The pump was set to a constant flow rate and frequency (1 mL / 100 g, 80 bpm). The change in airway pressure (corresponding to airway resistance at constant flow rate) was followed by an electromagnetic pressure transducer (Gould, France), which was connected to a shunt in the ventilation circuit and a potentiometric recorder (Gould) through an amplifier. Individual groups of animals received bolus doses of 10 mcg / kg histamine by injection via a catheterized jugular vein at intervals of 5 minutes until

-135 ··· *

pressure increased repeatedly. The test compounds were administered either intravenously at a single dose level and the agonist challenge was repeated every 30 minutes starting from the first minute after treatment for 1 minute or aerosolized directly into the respiratory tract.

Following the histamine test series, the respiratory system was coupled to a medical aerosol generating device (Devilbiss Pulmoid) containing a solution of the test compound. Thus, the animals were aerosolized directly into the respiratory tract (mean particle size 0.6 mcm) for 1-5 minutes.

The agonist challenge is then followed by 1. was repeated every 5 minutes for 30 minutes.

The amount of compound administered to the animal was expressed as the concentration of the solution and the time of spraying (e.g., 125 mcg / ml for 5 minutes).

The magnitude of the inhibition of compound-induced bronchospasm was estimated by the average of the filling pressures measured during the three histamine challenges prior to injection or spraying of the compound and the loading pressure after compound administration.

The amount of test compound administered to the animals in the present experiment is 250 micrograms / ml, sprayed for 5 minutes, and the results are summarized in the following table:

-136 · «·« · ·· * ··· • · · * · ·· ·· * · «*

V ί · «• t

Compound Inhibition of histamine-induced bronchoconstriction Peak effect (% change) 1. -46.0 + 13.3 Second -43.9 + 7.0

Compound 1: 6-nitro-2,2-dimethyl-3- (acetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran;

Compound 2: 6- (trifluoromethyl) -2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H- 1-benzopyran.

In this assay, compounds of the general formula (I) exhibit an exaggerating effect.

26.példa

In vivo examination of intraocular pressure in rabbits

These experiments were performed on young New Zealand albino rabbits weighing 2.0-3.0 kg, according to the method described by L. David Waterbury in Investigative Ophtalmology and Visual Science 31. 2560-2567 (1990). The rabbits were not allowed to receive any topical medicinal product prior to the study. Intraocular pressure (IOP) was measured using a (Digilab, Bio-Rad) pneumotonometer calibrated at the beginning and end of each study with a Digilab membrane sensor. Before the start of the experiments, the rabbits were accustomed to the test conditions, ie they were removed from the cages

-137and after anesthesia of the cornea with topical application of proparacaine monohydrochloride (Allergan, Irvine), no measurements were performed. The rabbits were then randomized into treatment groups of seven animals. During initial tonometric readings, rabbits with an IOP difference of more than 3 mmHg between eyes were excluded from the study. The test animals had a baseline IOP between 19 and 25 mmHg. The compounds were applied at a volume of 50 microliters to one eye, and a corresponding volume of vehicle was added to the other eye as a control. In a further group, animals received vehicle for both eyes. The IOP values of the compounds of formula I were compared with the IOP values of both rabbits treated with vehicle and rabbit treated with either eye. This second parameter allows the estimation of potential systemic effects. The intraocular pressure was measured one minute before and one to eight hours after compound application.

Eye irritation, eyelid closure, and blood congestion were recorded in each experiment. A dose response curve for each compound was prepared. Significance of treatment effect was determined by analysis of variance. The IOP values of compound treated eyes and eyes treated with the same rabbit vehicle were compared in pairs. In addition, the internal pressure of the vehicle-treated eyes in the control group was also compared with the internal pressure of the treated eyes. All statistics were analyzed using general linear models.

Compounds of formula -138Αζ in this assay lowered intraocular pressure and thus exhibited anti-glaucoma properties.

27.példa

Peripheral vascular ischemia in rat (In vivo determination)

This assay was performed on Sprague-Dawley rats weighing 140-150 g. The animals were anesthetized by intraperitoneal administration of 50 mg / kg pentobarbital and the left femoral artery was circumferentially occluded at the level of the iliac artery by a silk vein ligament, as described by Angersbach and Nicholson in Naunyn-Schmiedeberg's Arch. Pharmacol. 337, 341-346 (1988)]. The animals were allowed to recover for six weeks, during which time the lateral blood vessels developed in the clamped leg. Six weeks after confinement, the animals were re-anesthetized (55 mg / kg pentobarbital, i.p.), maintained at 1 mg / kg / h (i.v.) pentobarbital, and maintained at a constant temperature of 37 ° C. An arterial catheter was inserted into the carotid artery to measure blood pressure and heart rate, and a second catheter was inserted into the jugular vein for injection of test substances. The skin was removed from the inner surface of the left and right hind legs and on the inner surface of the egg to monitor the red blood cell flow in the local skeletal muscles.

Compounds of formula (I), administered intravenously by infusion, produced a progressive increase in red blood cell flow in the pineal leg in this model.

-139-

Example 28

In vitro determination of 5-lipoxygenase inhibitory activity

This assay was performed on whole human blood.

ml of freshly harvested heparin-treated blood and 2 microliters of a test compound solution (0.01-100 micrograms of test substance / ml) were preincubated at 37 ° C for 15 minutes. To initiate the reaction, A23187 (2 microliters, 25 mM) calcium ionophore was added. After 0 min incubation at 37 ° C, plasma was separated and analyzed by radioimmunoassay for leukotriene (LTB4) content and the results compared to the mean value of controls with dimethyl sulfoxide vehicle. For each assay, duplicate determinations were made.

Among the compounds of formula I, 6- (trifluoromethyl) -2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4 (2-oxo-1,2-dihydropyridin-1-yl) ) -2H-1-benzopyran was assayed according to the above procedure and the pICgg value was 4.3 (pICgQ = negative log [M], where [M] is the concentration of compound that is 50% of A23187-induced LTB4 stimulation. in).

Compound (I) showed 5-lipoxygenase inhibitory activity in this assay.

Example 29 Toxicity of a compound of formula (I) 6- (trifluoromethyl) -

2,2-Dimethyl-3- (N-hydroxyacetamidomethyl) - (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran was orally administered to rats (0.1- 1.0 mg / kg) and in combination with dosing • · ·

-140- no addictive mortality was observed. At non-hemodynamic doses, no clinical signs or pathological changes were observed. At the antihypertensive doses, pathological changes of the heart characteristic of such compounds having a pharmacological profile have been observed following reflex tachycardia and, inter alia (at the highest doses).

Although the present invention has been described with reference to certain specific embodiments thereof, it will be apparent to those skilled in the art that various modifications and equivalents may be made without departing from the spirit and scope of the invention. In addition, many modifications are possible to apply a particular situation, material, composition, process, process step or steps for the purpose, spirit or scope of the invention. Any such modification is within the scope of the following claims.

Claims (37)

Patent claims: Compounds of the formula I in which r 1 and ^R2 are independently selected form hydrogen or lower alkyl or together with the carbon atom to which they are attached C3-8 cycloalkyl; R ^{3 is} hydrogen, halo, fluoroalkyl, lower cyano, or nitro; R ⁴ (a), (b) or (c) a group of formula R5 and R® independently hydrogen or lower alkyl; and R? -ΝΚθΕθ is a group in which R is hydrogen, lower alkyl, lower alkoxy, hydroxy or lower hydroxyalkyl; and Βθ is hydrogen, lower alkyl, lower hydroxyalkyl, -SO ₂ R ¹⁰ , -CO ₂ R ¹⁰ , -C (O) NR ¹¹ R ¹² , -C (S) NR ¹¹ R ¹² or -C ( O) ^R12 group a generic formula wherein Rio is lower alkyl; rH is hydrogen or lower alkyl; and R ^{12 is} hydrogen, lower alkyl or lower fluoroalkyl; Q _x Q with the proviso that one of R 0 and R ^J cannot be hydrogen; or a pharmaceutically acceptable salt thereof. r c Compounds according to claim 2.1 wherein R 0 and R ^{D are} hydrogen or a pharmaceutically acceptable salt thereof. -142- 3.2. Compounds according to claim 1, wherein R ⁴ and R ² are each methyl or a pharmaceutically acceptable salt thereof. The compound of claim 3, wherein R ^{4 is} 2-oxo-1,2-dihydropyridin-1-yl, or a pharmaceutically acceptable salt thereof. Compounds according to claim 4, wherein R ^{8 is} hydrogen, hydroxy or lower alkoxy and R ^{9 is} hydrogen, lower alkyl or -C (O) R 1 - ^L or a pharmaceutically acceptable salt thereof. 6. A compound according to claim ⁵ wherein R ^{8 is} hydrogen. Q 19 and R ³ , or pharmaceutically acceptable salts thereof. The compound of claim 6, wherein R ^{3 is} nitro and hydrogen, i.e., 6-nitro-2,2-dimethyl-3- (formamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) - 2H-1-benzopyran or pharmaceutically acceptable salts thereof. The compound of claim 6, wherein R ^{3 is} nitro and R ^{14 is} methyl, i.e. 6-nitro-2,2-dimethyl-3- (acetamidomethyl) -4- (2-oxo-1,2-dihydropyridine-1-). ii) -2H-1-benzopyran or pharmaceutically acceptable salts thereof. The compound of claim 6, wherein R ^{3 is} nitro and R ^{1 is} trifluoromethyl, i.e. 6-nitro-2,2-dimethyl-3 (trifluoroacetamidomethyl) - (2-oxo-1,2) -dihydropyridin-1-yl) 2H-1-benzopyran or pharmaceutically acceptable salts thereof. The compound of claim 6, wherein R is trifluoro 1 to 9 methyl groups and ^{1 to} 4 hydrogen atoms, i.e. 6- (trifluoromethyl) - 2,2-dimethyl-3- (formamido) methyl-4- (2-oxo-l, 2-dihydropyridine -143- 1-yl) -2H-1-benzopyran or pharmaceutically acceptable salts thereof. A compound according to claim 6 wherein R ^{3 is} trifluoromethyl and R ^{2 is} methyl, i.e. 6- (trifluoromethyl) - 2,2-dimethyl-3- (acetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran or pharmaceutically acceptable salts thereof. o - | She A compound according to claim 6, wherein R 0 and R 2 are both trifluoromethyl, i.e. 6- (trifluoromethyl) - 2,2-Dimethyl-3- (trifluoroacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran or pharmaceutically acceptable salts thereof. q Compounds according to claim 5, wherein R 0 is a hydroxy group or a pharmaceutically acceptable salt thereof. The compound of claim 13, wherein R is nitro and R ^{8 is} hydrogen, i.e., 6-nitro-2,2-dimethyl-3- (hydroxyaminomethyl) -4- (2-oxo-1,2-dihydropyridine-1-). ii) -2H-1-benzopyran or pharmaceutically acceptable salts thereof. 15. A compound according 13.igénypont wherein R ⁸ C (O) R ² group of formula I or pharmaceutically acceptable salts thereof. She A compound according to claim 15 wherein R is nitro and R ^{2 is} methyl, i.e. 6-nitro-2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1,2-dihydropyridine) -1-yl) -2H-1-benzopyran or pharmaceutically acceptable salts thereof. q 17. A compound according to claim 15, wherein R i and R ² -CN methyl, namely 6-cyano-2,2-dimethyl-3- (N-hydroxyacetamido) methyl-4- (2-oxo-l, 2-dihydropyridin 1-yl) -2H-1-benzopyran or pharmaceutically acceptable salts thereof. She The compound of claim 15, wherein R 0 is trifluoromethyl and R ^{2 is} methyl, i.e., 6- (trifluoromethyl) -144-. 2,2-Dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran or pharmaceutically acceptable salts thereof. 19. A compound according to claim 15, wherein R ³ pentafluoroethyl and R ^x = methyl group, i.e., 6- (pentafluoi-ethyl) - 2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran or pharmaceutically acceptable salts thereof. The compound of claim 15, wherein R 1 'is ³ halogen atoms or pharmaceutically acceptable salts thereof. A compound according to claim 20, wherein R ^{3 is} bromo and R ^{12 is} methyl, i.e. 6-bromo-2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1), 2-dihydropyridin-1-yl) -2H-1-benzopyran or pharmaceutically acceptable salts thereof. 20.igénypont compound 22 wherein R ² is chloro and R j is methyl, namely 6-chloro-2,2-dimethyl-3- (N-hydroxyacetamido) methyl-4- (2-oxo-l, 2-dihydropyridin 1-yl) -2H-1-benzopyran or pharmaceutically acceptable salts thereof. She A compound according to claim 20 wherein R is bromo and R ^{12 is} ethyl, i.e., 6-bromo-2,2-dimethyl-3- (N-hydroxypropionamidomethyl) -4- (2-oxo-1,2- dihydropyridin-1-yl) -2H-1-benzopyran or pharmaceutically acceptable salts thereof. p Compounds according to claim 5, wherein R is lower alkoxy and R ^{8 is} hydrogen or a pharmaceutically acceptable salt thereof. She 25. A compound according to claim 24 wherein R 0 is nitro and R ^{8 is} methoxy, i.e. 6-nitro-2,2-dimethyl-3- (methoxaminomethyl) -4- (2-oxo-1,2-dihydropyridin-1). -yl) -2H-1-benzopyran or pharmaceutically acceptable salts thereof. • · · · «·« · -145- 26. A compound according 3.igénypont wherein R ⁴ 2-oxopyrrolidin-l-yl or a pharmaceutically acceptable salt thereof. 27. A compound according 26.igénypont wherein R ² is hydrogen or hydroxy and R ² is hydrogen, lower alkyl or -C (O) R ⁴² group of formula or a pharmaceutically acceptable salt thereof. 28. A compound according to claim ³ wherein R ^{4 is} 1-oxoisoindolin-2-yl or a pharmaceutically acceptable salt thereof. 29. A compound according 28.igénypont wherein R ² is hydrogen or hydroxy and R ² is hydrogen, lower alkyl or -C (O) R ⁴² group of formula or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable non-toxic carriers. 31. A method of treating diseases in mammals that can be ameliorated by potassium channel activator or 5lipoxygenase inhibitor, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. 32. A method of treating mammalian diseases that can be ameliorated by potassium channel activator, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. 33. The method of claim 32 wherein the condition is hypertension, congestive heart failure, angina, peripheral -146- coronary artery disease, coronary artery and cerebral spasm, smooth muscle spasm, seizure, hypersensitive bowel syndrome, premature birth, menstrual disorder, incontinence, renal failure, urinary retention, cardiac arrhythmias, reversible asthma, reversible asthma 34. The method of claim 33, wherein the condition is hypertension, reversible airway obstruction, or asthma. 35. The method of claim 34, wherein the compound of claim 1 is a member of the group: 6-nitro-2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran; 6- (trifluoromethyl) -2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran; 6-cyano-2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran; 6- (pentafluoroethyl) -2,2-dimethyl-3- (N-hydroxyacetamidomethyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran; 6-nitro-2,2-dimethyl-3- (acetamido) methyl-4- (2-oxo-2dihidropiridin-l-yl) -2H-1-benzopyran; 6-nitro-2,2-dimethyl-3- (formamido) methyl-4- (2-oxo-2dihidropiridin-l-yl) -2H-l-benzopyran; 6-bromo-2,2-dimethyl-3- (N-acetamidomethyl) -4- (2-oxo-l, 2-dihydro-l-yl) -2H-1-benzopyran; 6-chloro-2,2-dimethyl-3- (N-hydroxyacetamido) methyl-4- (2-oxo-1,2-dihydropyridin-l-yl) -2H-l-benzopyran; and 6-bromo-2,2-dimethyl-3- (N-hydroxypropionamido-methyl) -4- (2-oxo-1,2-dihydropyridin-1-yl) -2H-1-benzopyran; or gyo-147 ♦ ·· ♦ 4 4 «« 4 · «4 ···· 4 · 44 * 44 «·· their pharmaceutically acceptable salts. 36. A method of treating a mammal wherein the condition is selected from the group consisting of hypertension, congestive heart failure, angina, peripheral arterial occlusion disease, coronary artery spasms, smooth muscle spasms, seizures, hypersensitivity bowel syndrome, premature childbirth, menstrual disorders, , reversible respiratory tract obstruction, asthma, cardiac arrhythmia, myocardial infarction, ischemic heart disease, glaucoma, epilepsy, psycho-depressive states, baldness, proliferative diseases, obesity, rheumatoid arthritis, osteoarthritis, osteoarthritis, mucous membrane, psoriasis or ulcerative colitis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. 37. A process for the preparation of a compound of formula (I) R ¹ and R 4 are each independently hydrogen or lower alkyl, or together with the carbon to which they are attached form a C 3 -C 8 cycloalkyl; r3 is hydrogen, halogen, lower-carbon fluoroalkyl, cyano or nitro; R 4 is (a), (b) or (c); r5 and r6 are each independently hydrogen or lower alkyl; and R? -Nr8r9, where * ··· * 4 «« 44 «« • · ··· -148R ⁸ is lower alkyl, lower alkyl or lower alkyl alkoxicsosport hydroxyalkyl; and R ^{8 is} hydrogen, lower alkyl, lower hydroxyalkyl, a) reacting a compound of Formula 14 with an amine of Formula HNR ⁸ R ⁸ wherein R 0 and R ³ are as defined above; obsession b) reacting a compound of formula (15) or (IA) with a lower alkyl formate to give a compound of formula (I) wherein R, R, R, R ⁴ , R ⁸ , R ⁸ , R ⁷ and R ⁸ is as defined above and R ^{8 is} -C (O) R ⁴² wherein R is hydrogen; obsession c) reacting a compound of formula (15) or (IA) with a compound of formula WSC ^ R ⁴⁸ or WCC ^ R ^{48 in} which W is chlorine or bromine and R ^{48 is a} lower alkyl group such as a compound of formula I wherein R ⁴ , R ² , R ³ , R ⁴ , R ⁸ , R ⁸ , R ⁷ and R ⁸ are as defined above and R ^{8 is} -SC ^ R ⁴⁸ or -CC ^ R ⁴⁸ wherein R ⁴⁸ has the meaning given above; obsession d) reacting a compound of formula (15) or (IA) with a compound of formula WCO _R ⁴² or (R ⁴² CO) 2 O, wherein W is chloro or bromo and R ^{42 is} lower alkyl or lower fluoroalkyl; to give compounds of formula I wherein R ⁴ , R ² , R ³ , R ⁴ , R ⁸ , R ⁸ , R ⁷ and R ⁸ are as defined above and R ^{8 is} -C (O) R ^42. general -149- 1 Ρ> ·, as defined above; obsession e) a compound of formula (15) or (IA) Toilet (0) NrUrI-2 _va w WC (S) is reacted with NR -1r12 compound, this latter formula wherein W is chloro or bromo, R ^{± X} is lower alkyl and ^R1 ^ is lower alkyl or lower alkyl fluoroalkyl group to give compounds of formula I wherein R 1, R ² , R ² , R ² , R ² , R ² , R ² and R ⁸ is as defined above and R ^{8 is} -C (O) NR 1 - ² R ² - ² , wherein R 1 - ² is as defined above; obsession f) one (15) or (IA) with a compound rIZnCO or R ^ NCS is reacted with a compound of formula, the latter formulas, R · ² represents lower alkyl or lower alkyl fluoro groups such as (I) where R 1, R ² , R ² , R ² , R ² , R ² are obtained. , R? and R ⁸ is as defined above for R ⁹ -C (O) NHR ¹² or -C (S) NHR ¹² 1 2 groups wherein R is as defined above; obsession g) reacting a compound of formula (15) or (IA) with a trialkylsilyl isocyanate or a trialkylsilyl isothiocyanate to give a compound of general formula (I) wherein R 1 is. R ² , R ² , R 4, R ⁴ , R 4, R ² ? and R ⁸ is as defined above and R ⁸ -C (O) NHR · '· ² or -C (S) NHR ^ · ² group of formula, R is hydrogen; h) reacting a compound of Formula 19 with an alkali metal hydride; obsession i) reacting a free base of formula (I) with an acid to form a pharmaceutically acceptable acid addition salt; obsession -150- j) reacting the acid addition salt of a compound of formula I with a base to form the corresponding free base; obsession k) converting an acid addition salt of a compound of formula I into another pharmaceutically acceptable acid addition salt.